Bicyclic compound and use thereof for medical purposes

ABSTRACT

Since a compound represented by the general formula (I) (wherein definition of each group is as described in the specification), a salt thereof, a solvate thereof, or a prodrug thereof has strong and sustaining intraocular pressure lowering activity and, further, has no side effect on eyes such as ocular stimulating property (hyperemia, corneal clouding etc.), aqueous humor protein rise etc., it has high safety, and can be an excellent agent for preventing and/or treating glaucoma etc.

TECHNICAL FIELD

The present invention relates to a compound represented by the generalformula (I)

(wherein all symbols represent the same meanings as those describedbelow), a salt thereof, or a solvate thereof, or a prodrug thereof(hereinafter, abbreviated as present invention compound in some cases).

BACKGROUND OF ART

Glaucoma is an ocular disease having the characteristic of a visualfunctional disorder which causes a transient or permanent visual fielddefect and decreased vision.

This is derived from that since an aqueous humor is accumulated by acirculatory disorder of an aqueous humor, and an intraocular pressure iscontinuously increased, an optic nerve is compressed. Decrease in anintraocular pressure is effective for treatment of glaucoma and, inorder to decrease an intraocular pressure, for example, drug treatment(eye drops, internal remedy, infusion treatment), laser treatment, oroperation treatment is performed.

Previously, among prostaglandins (PGs) which are physiologically activesubstances, as those that decrease an intraocular pressure, PGFs andPGIs are known. Development of a drug for treating glaucoma or ocularhypertension is being progressed using derivatives of them, and thereare some drugs which are actually sold (e.g. latanoprost etc.). However,the existing glaucoma treating drug alone is insufficient in intraocularpressure lowering action and sustainability of drug efficacy and, in atsite of glaucoma treatment, since administration at a frequent time or ahigh concentration, or therapy of joint use of drugs having differentmechanisms of action are being performed seeking stronger intraocularpressure lowering action, manifestation of side effects is feared. Forthis reason, drugs having stronger and sustaining intraocular pressurelowering action, and high safety are desired.

Meanwhile, as the prior art of the present invention compound, thefollowing PG derivatives are exemplified.

As a PG derivative having a bicyclic skeleton, for example, a compoundof the general formula (a):

etc., L^(a) is —(CH₂)_(da)—C(R^(2a))₂— (wherein da is 0 to 5, andR^(2a)s are hydrogen, methyl or fluoro, and are the same or different)etc., Q^(a) is an oxygen atom etc., R^(1a) is COOR^(3a) (wherein R^(3a)is hydrogen, alkyl of 1 to 12 carbon atoms etc.) etc., R^(4a) is:

(wherein R^(5a) and R^(6a) are hydrogen, alkyl of 1 to 4 carbon atoms orfluoro, and are the same or different, Z^(a) is an oxygen atom etc.,T^(a) is alkyl of 1 to 4 carbon atoms, fluoro, chloro etc., and sa is 0to 3) etc., V^(a) is a valence bond or —CH₂, W^(a) is —(CH₂)_(h), h is 1or 2, X^(a) is trans-CH═CH— etc. (a part of definitions of groups wasextracted) is known (see Patent Literature 1).

In addition, a compound represented by the general formula (b):

(wherein L^(b) represents —(CH₂)_(db)— (wherein db represents 1 to 5)etc., Q^(2b) represents O etc., R^(1b) represents —COOR^(19b) (whereinR^(19b) represents a C1-C12 alkyl group or a hydrogen atom etc.) etc., aring R^(22b) represents:

(wherein R^(4b) represents a hydrogen atom etc.) etc., R^(25b)represents:

(wherein R^(5b) and R^(6b) represent a hydrogen atom etc., Z^(b)represents —O— etc., T^(b) represents a C1-4 alkyl group, fluorine,chlorine, trifluoromethyl or —OR^(7b)— (wherein R^(7b) represents C1-4alkyl), sb represents 0, 1, 2 or 3, and X^(b) represents:

(a part of definitions of groups was extracted)) (see Patent Literature2) is known.

Further, a process for producing a compound represented by the generalformula (c):

(wherein A^(c) represents a C1-2 alkylene group, B^(c) represents a C2-6alkylene group, XC represents C(O) etc., and Z^(c) represents a C1-4alkylene group etc. (a part of definitions of groups was extracted)) isknown (see Patent Literature 3).

Meanwhile, it has been reported that agonistic activity on an IPreceptor among PG receptors causes hyperemia and rise in a aqueous humorprotein, and inducement of stimulation on eyes has been feared (seeNon-Patent Literatures 1 and 2). For this reason, since the compounddescribed in Patent Literature 2 which is a PGI2 derivative hasagonistic activity on an IP receptor, there is a probability thatproperty of stimulating eyes etc. are induced.

Further, it has been also known that agonistic activity on an EP1receptor among PGE subtype receptors causes itching of eyes (seeNon-Patent Literature 3).

The present invention compound is a compound which has low agonisticactivity on an IP receptor and an EP1 receptor, and has selectiveagonistic activity on a FP receptor, but there is neither thedescription nor the suggestion regarding such the characteristic(selectivity) in any prior arts.

PRIOR ART LITERATURES Patent Literatures

-   Patent Literature 1: JP-A No. 52-95644 gazette-   Patent Literature 2: U.S. Pat. No. 4,490,548-   Patent Literature 3: JP-A No. 50-37780 gazette

Non-Patent Literatures

-   Non-Patent Literature 1: Investigative Ophthalmology & Visual    Science, Vol. 28, p. 470-476, 1987-   Non-Patent Literature 2: Investigative Ophthalmology & Visual    Science, Vol. 23, p. 383-392, 1982-   Non-Patent Literature 3: The Journal of Pharmacology and    Experimental Therapeutics, Vol. 279, No. 1, p. 137-142, 1996

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

A compound which has strong and sustaining intraocular pressure loweringaction and, further, has no fear of side effects on eyes is desired.

Means to Solve the Problems

In order to solve the aforementioned problems, the present inventorsintensively studied to find out a compound which has improvedselectivity on a PG receptor subtype, that is, a compound which has lowagonistic activity on an IP receptor and an EP1 receptor, and hasselective agonistic activity on a FP receptor and, as a result,completed the present invention.

That is, the present invention relates to:

1. A compound represented by the general formula (I):

(wherein R¹ represents (1) COOH, (2) COOR², (3) CH₂OH, or (4) CONR³R⁴,R² represents a C1-C6 alkyl group optionally substituted with a hydroxygroup, ONO₂ or a C1-4 alkoxy group, R³ and R⁴ each representindependently a hydrogen atom, or a C1-4 alkyl group optionallysubstituted with ONO₂, R⁵ represents a halogen atom, a hydroxy group, ora C1-4 alkoxy group, Z represents (1) —(CH₂)_(m)—, (2)—(CH₂)_(n)—CH═CH—, (3) —(CH₂)_(p)-A-CH₂—, or (4) ring 1, A represents anoxygen atom, or a sulfur atom, W represents a C1-6 alkyl groupoptionally substituted with 1 to 5 substituents selected from the groupconsisting of (1) a hydroxy group, (2) an oxo group, (3) a halogen atom,(4) a C1-4 alkyl group, (5) a C1-4 alkoxy group, (6) ring 2, (7) —O-ring2, and (8) —S-ring 2, ring 1 and ring 2 each represent independently aC3-10 carbocycle or a 3- to 10-membered heterocycle, optionallysubstituted with 1 to 5 substituents selected from the group consistingof (1) a halogen atom, (2) CF₃, (3) OCF₃, (4) a C1-4 alkoxy group, (5) aC1-4 alkyl group, (6) a hydroxy group, and (7) a nitrile group, mrepresents an integer of 1 to 6, n represents an integer of 1 to 4, prepresents an integer of 1 to 4,

[Chemical Formula 12]

represents a single bond or a double bond,

[Chemical Formula 13]

represents α configuration,

[Chemical Formula 14]

represents β configuration,

[Chemical Formula 15]

represents α configuration, β configuration or an arbitrary mixture ofthem), or a salt thereof, a solvate thereof, or a prodrug thereof,2. The compound according to 1, represented by the general formula(I-1):

(wherein all symbols represent the same meanings as those described in1), or a salt thereof, a solvate thereof, or a prodrug thereof,3. The compound according to 2, represented by the general formula(I-2):

(wherein R⁶ and R⁷ each represent independently a hydrogen atom, ahydroxy group, a halogen atom, a C1-4 alkyl group or a C1-4 alkoxygroup, R⁶ and R⁷ may be taken together to form an oxo group, Yrepresents —CH₂—, —O— or —S—, and other symbols represent the samemeanings as those described in 1), or a salt thereof, a solvate thereof,or a prodrug thereof,4. The compound according to 3, wherein the ring 2 is a C3-7 carbocycle,or a salt thereof, a solvate thereof, or a prodrug thereof,5. The compound according to 3, wherein Z is (1) —(CH₂)_(m)—, or (2)—(CH₂)_(p)-A-CH₂— (all symbols represent the same meanings as thosedescribed 1), or a salt thereof, a solvate thereof, or a prodrugthereof,6. The compound according to 3, wherein the compound represented by thegeneral formula (I-2) is a compound selected from:

-   (1) 4-{(3 S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,    3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoic    acid,-   (2) ethyl 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,    3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate,-   (3) 2-propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,    3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate,-   (4) 4-{(3 S, 5aR, 6R, 7R, 8aS)-6-[(1E,    3R)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoic    acid,-   (5) 2-propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,    3R)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate,-   (6) 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,    3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoic    acid, and-   (7) 2-propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,    3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate,    a salt thereof, a solvate thereof, or a prodrug thereof,    7. A pharmaceutical composition comprising the compound represented    by the general formula (I) according to 1, or a salt thereof, a    solvate thereof, or a prodrug thereof,    8. The pharmaceutical composition according to 7, which is a FP    agonist,    9. The pharmaceutical composition according to 7, which is an agent    for preventing and/or treating an ocular disease,    10. The pharmaceutical composition according to 9, wherein the    ocular disease is glaucoma, ocular hypertension, macular edema,    macular degeneration, retina and optic nerve tensile force rise,    myopia, hypermetropia, astigma, dry eye, amotio retinae, cataract,    intraocular pressure rise due to trauma or inflammation, intraocular    pressure rise due to a drug, or intraocular pressure rise after    operation,    11. A method of preventing and treating an ocular disease,    comprising administering an effective amount of the compound    represented by the general formula (I) according to 1, or a salt    thereof, a solvate thereof, or a prodrug thereof to a mammal,    12. The compound represented by the general formula (I) according to    1, or a salt thereof, a solvate thereof, or a prodrug thereof, for    preventing and/or treating an ocular disease and,    13. The compound represented by the general formula (I) according to    1, or a salt thereof, a solvate thereof, or a prodrug thereof, for    producing an agent for preventing and/or treating an ocular disease.

Effect of the Invention

The present invention compound has strong and sustained intraocularpressure lowering action, and is useful as a therapeutic agent forglaucoma having no side effect on eyes such as ocular stimulatingproperty (hyperemia, cloudy cornea etc.), humor protein rise etc.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 A graph expressing transition of ocular stimulating propertybased on the Draize score after ocular instillation of the presentinvention compound and a comparative compound.

FIG. 2 A graph expressing transition of a concentration of a protein ina humor after ocular instillation of the present invention compound anda comparative compound.

FIG. 3 Shows a powder X-ray diffraction spectral chart of a crystal ofthe present invention compound (Example A).

FIG. 4 Shows a differential scanning calorimetry (DSC) of a crystal ofthe present invention compound (Example A).

FIG. 5 Shows a powder X-ray diffraction spectral chart of a crystal ofthe present invention compound (Example B).

FIG. 6 Shows a differential scanning calorimetry (DSC) chart of acrystal of the present invention compound (Example B).

FIG. 7 Shows a powder X-ray diffraction spectral chart of a crystal ofthe present invention compound (Example C).

FIG. 8 Shows a powder X-ray diffraction spectral chart of a crystal ofthe present invention compound (Example D).

FIG. 9 Shows a differential scanning calorimetry (DSC) chart of acrystal of the present invention compound (Example D).

FIG. 10 Shows a powder X-ray diffraction spectral chart of a crystal ofthe present invention compound (Example E).

FIG. 11 Shows a differential scanning calorimetry (DSC) chart of acrystal of the present invention compound (Example E).

FIG. 12 Shows a powder X-ray diffraction spectral chart of a crystal ofthe present invention compound (Example F).

FIG. 13 Shows a differential scanning calorimetry (DSC) chart of acrystal of the present invention compound (Example F).

MODE FOR CARRYING OUT THE INVENTION

The present invention will be explained in detail below.

In the present invention, the C1-6 alkyl group means a straight orbranched C1-6 alkyl group such as methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl,hexyl etc.

In the present invention, the C1-4 alkyl group means a straight orbranched C1-4 alkyl group such as methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, tert-butyl etc.

In the present invention, the C1-4 alkoxy group means a straight orbranched C1-4 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutyloxy, tert-butoxy etc.

In the present invention, the halogen atom means fluorine, chlorine,bromine, and iodine.

In the present invention, the C3-10 carbocycle means a C3-10 monocyclicor bicyclic carbocycle, a part or all of which may be saturated, andexamples include cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene,cyclohexne, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene,cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene,azulene, perhydroazulene, indene, perhydroindene, indane,perhydroindane, naphthalene, dihydronaphthalene, tetrahydronaphthalene,perhydronaphthalene etc.

In the present invention, the C3-7 carbocycle means a C3-7 monocycliccarbocycle, a part or all of which may be saturated, and examplesinclude cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene,cyclohexadiene, cycloheptadiene, benzene, etc.

In the present invention, the 3- to 10-membered heterocycle means a 3-to 10-membered monocyclic or bicyclic heterocycle, a part or all ofwhich may be saturated, comprising 1 to 5 hetero atoms selected from anoxygen atom, a nitrogen atom and a sulfur atom, and examples includepyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,thiophene, thiopyran, thiepine, oxazole, isooxazole, thiazole,isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, aziridine, azetidine, pyrroline, pyrrolidine,imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline,tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine),dihydroisooxazole, tetrahydroisooxazole (isooxazolidine),dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, dithiane,indole, isoindole, indolizine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, dithianaphthalene, indazole,quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine,naphthyridine, quinoxaline, quinazoline, cinnoline, pyrrolopyridine,benzoxazole, benzothiazole, benzimidazole, chromene, indoline,isoindoline, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,tetrahydropyrrolopyridine, dihydrocinnoline, tetrahydrocinnoline,perhydrocinnnoline, benzoxathiane, dihydrobenzoxazine,dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, and perhydrobenzimidazole.

In the present invention, the sulfur atom in A includes an oxidizedsulfur atom, that is, —SO— or —SO₂— in addition to —S—.

In the present invention, as R², methyl, ethyl, propyl, or isopropyl ispreferable.

In the present invention, as R⁵, a hydroxy group, or a halogen atom ispreferable.

In the present invention, as Z, —(CH₂)_(m)—, —(CH₂)_(n)—CH═CH—,—(CH₂)_(p)-A-CH₂—, or ring 1 is preferable, and —(CH₂)_(m)—, or—(CH₂)_(p)-A-CH₂— is more preferable. Herein, as A, an oxygen atom ispreferable.

In the present invention, as the “C1-6 alkyl group” represented by W, anethyl group, or a propyl group is preferable. Herein, as a substituentof the “C1-6 alkyl group”, a hydroxy group, an oxo group, a halogenatom, a C1-4 alkyl group, a C1-4 alkoxy group, —O-ring 2 or ring 2 ispreferable.

In the present invention, as the ring 1, benzene or a thiazole ring ispreferable.

In the present invention, as the ring 2, a C3- to C7-membered carbocycleis preferable, and benzene, or a cyclohexane ring is more preferable.Herein, as a substituent of the ring 2, a C1-4 alkyl group, a C1-4alkoxy group, CF₃, OCF₃ or a halogen atom is preferable, and a C1-4alkyl group, CF₃, OCF₃ or a halogen atom is more preferable.

In the present invention, as m, an integer of 2 to 4 is preferable.

In the present invention, as n, 1 is preferable.

In the present invention, the a chain means a side chain binding to a7-membered ring, and the ω chain means a side chain binding to a5-membered ring, in each general formula.

In the present invention, among the compound represented by the generalformula (I), a compound represented by the general formula (I-1):

(wherein all symbols represent the same meanings as those describedabove), or a compound represented by the general formula (I-1-1):

(wherein all symbols represent the same meanings as those describedabove) is preferable, a compound represented by the general formula(I-2):

(wherein all symbols represent the same meanings as those describedabove), or a compound represented by the general formula (I-2-1)

(wherein all symbols represent the same meanings as those describedabove) is more preferable. Herein, as R⁶ and R⁷, a hydrogen atom, ahalogen atom or a hydroxy group is preferable and, as Y, —O— ispreferable.

[Isomer]

In the present invention, an isomer includes all isomers unlessotherwise is indicated. For example, the alkyl group includes a straightalkyl group and a branched alkyl group. Further, all of an isomer at adouble bond, a ring, or a condensed ring (E isomer, Z isomer, cisisomer, trans isomer), an isomer due to the presence of an asymmetriccarbon etc. (R, S isomer, α, β configuration, enantiomer, diastereomer),an optically active body having optical rotation (D, L, d, 1 isomer), apolar body derived from chromatographic separation (high polar compound,low polar compound), an equilibrated compound, a rotation isomer, amixture of them at an arbitrary ratio, and a racemic mixture areincluded in the present invention. In addition, in the presentinvention, the isomer includes all isomers derived from tautomers.

In addition, the optically active compound in the present invention mayinclude not only 100% pure compounds, but also other optical isomers ordiastereomers which are less than 50% pure.

In the present invention, unless otherwise is indicated, as is apparentto a person skilled in the art, a symbol:

[Chemical Formula 22]

represents that a group is bound to another side of a paper plane (i.e.α configuration),

[Chemical Formula 23]

represents that a group is bound to a front side of a paper plane (i.e.β configuration),

[Chemical Formula 24]

represents α configuration, β configuration or a mixture thereof, and

[Chemical Formula 25]

represents a mixture of α configuration and β configuration.

The compound represented by the general formula (I) is converted into acorresponding salt by the known method. As the salt, a water-solublesalt is preferable. Examples of a suitable salt include salts of analkali metal (potassium, sodium etc.), salts of an alkaline earth metal(calcium, magnesium etc.), ammonium salts, salts of pharmaceuticallyacceptable organic amine (tetramethylammonium, triethylamine,methylamine, dimethylamine, cyclopentylamine, benzylamine,phenethylamine, piperidine, monoethanolamine, diethanolamine,tris(hydroxymethyl)aminomethane, lysine, arginine, N-methyl-D-glucamineetc.) etc.

The compound represented by the general formula (I) and a salt thereofcan be also converted into a solvate. It is preferable that the solvateis low-toxic and water-soluble. Examples of a suitable solvate includesolvates with, for example, water, or alcohol-based solvents (e.g.ethanol etc.).

In addition, a prodrug of the compound represented by the generalformula (I) refers to a compound which is converted into the compoundrepresented by the general formula (I) by a reaction with an enzyme orgastric acid in a living body. Examples of the prodrug of the compoundrepresented by the general formula (I), when the compound represented bythe general formula (I) has a hydroxy group, include compounds in whicha hydroxy group is acylated, alkylated, phosphorylated, or boronized(e.g. compounds in which a hydroxy group of the present inventioncompound is acetylated, palmitoylated, propanoylated, pivaloylated,succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonizedetc.); compounds in which a carboxyl group of the compound representedby the general formula (I) is esterified, or amidated (e.g. compounds inwhich a carboxyl group of the compound represented by the generalformula (I) is ethyl-esterified, isopropyl-esterified,phenyl-esterified, carboxymethyl-esterified,dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified,ethoxycarbonyloxyethyl-esterified, phthalidyl-esterified,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterified,cyclohexyloxycarbonylethyl-esterified, or methylamidated) etc. Thesecompounds can be produced by the known method. In addition, the prodrugof the compound represented by the general formula (I) may be any of ahydrate and a non-hydrate. In addition, the prodrug of the compoundrepresented by the general formula (I) may be a prodrug which is changedto the compound represented by the general formula (I) under thephysiological condition, as described in “Development of Medicaments”published in 1990 by Hirokawa-Shoten Ltd., Vol. 7, “Molecular Design”,p. 163-198. Further, the compound represented by the general formula (I)may be labeled with an isotopic element (e.g. ²H, ³H, ¹¹C, ¹³C, ¹⁴C,¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, ¹²⁵I etc.) etc.

Particularly, examples of a preferable prodrug of the compoundrepresented by the general formula (I), upon ocular instillationadministration of the compound represented by the general formula (I),include compounds in which a carboxyl group possessed by the compoundrepresented by the general formula (I) is methyl-esterified,ethyl-esterified, propyl-esterified, isopropyl-esterified,butyl-esterified, isobutyl-esterified, sec-butyl-esterified,tert-butyl-esterified, pentyl-esterified, isopentyl-esterified,neopentyl-esterified, cyclopentyl-esterified, hexyl-esterified,cyclohexyl-esterified, trifluoroethyl-esterified, phenyl-esterified,carboxymethyl-esterified, dimethylaminomethyl-esterified,pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified,phthalidyl-esterified,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterified,cyclohexyloxycarbonylethyl-esterified, or methylamidated etc.

[Process for Producing Present Invention Compound]

The present invention compound can be produced by the known method, forexample, the method described in Comprehensive Organic Transformations:A Guide to Functional Group Preparations 2^(nd) Edition (Richard C.Larock, John Wiley & Sons Inc, 1999), or can be produced byappropriately improving the methods shown in Examples, and using acombination of them.

Among the compound represented by the general formula (I), a compound inwhich

[Chemical Formula 26]

are as described below, respectively, an α chain represents βconfiguration, R¹ represents COOR², R⁵ represents a hydroxy group, andone of R⁶ and R⁷ represents hydrogen, and the other represents a hydroxygroup, in the compound represents by general formula (I-2), that is, acompound represented by the general formula (I-2-a):

(wherein all symbols represent the same meanings as those describedabove) can be produced using a compound represented by the generalformula (II):

(wherein T¹ represents a protective group of a hydroxy group (e.g.2-tetrahydropyranyl (THP) group, p-phenylbenzoyl group etc.), and othersymbols represent the same meanings as those described above) as astarting substance, according to the following reaction step formula 1.

(wherein R¹⁰¹ represents a C1-6 alkyl group, and other symbols representthe same meanings as those described above)

In the reaction step formula 1, the reaction 1 is known and, forexample, is performed by reacting a compound represented by the generalformula (II) and a compound represented by the general formula (III) ata temperature of −20 to 70° C. in an organic solvent (e.g.tetrahydrofuran (THF), dimethylformamide (DMF), dimethoxyethane (DME),dioxane, acetonitrile, ethanol, dichloromethane etc.) or in water, or ina mixed solution thereof, in the presence of a base (e.g. sodiumhydride, sodium hydroxide, potassium hydroxide, potassium phosphate,potassium tert-butoxide, potassium carbonate, tertiary amine+lithiumchloride etc.).

In the reaction step formula 1, the reaction 2 is known, and isperformed by reacting the compound represented by the general formula(IV) obtained in the reaction 1 at −20 to 50° C. in an organic solvent(e.g. THF, DME, toluene, dichloromethane, diethyl ether, dioxane etc.),in the presence or the absence of cerium chloride using a reducing agent(e.g. sodium borohydride, zinc borohydride etc.). In addition, when onlyone of steric isomers is selectively produced, the reaction is performedat a temperature of −100 to 50° C. using an asymmetric reducing agent(e.g. chlorodiisopinocamphenylborane etc.), or a combination of anasymmetric aid and a reducing agent ((R)-2-methyl-CBS-oxazaborolidineand boron hydride, tetrahydrofuran complex or boranedimethyl sulfidecomplex, (S)-(−)-binaphthol and lithium aluminum hydride etc.).

In the reaction step formula 1, a reaction of deprotecting a protectivegroup is known, and can be performed by the following step. Examplesinclude (1) a deprotection reaction by alkali hydrolysis, (2) adeprotection reaction under the acidic condition, (3) a deprotectionreaction by hydrogenation degradation, (4) a deprotection reaction of asilyl group, (5) a deprotection reaction using a metal, (6) adeprotection reaction using a metal complex etc.

To specifically explain these methods,

The (1) deprotection reaction by alkali hydrolysis is performed, forexample, at 0 to 40° C. in an organic solvent (e.g. methanol,tetrahydrofuran, dioxane etc.), using a hydroxide of an alkali metal(e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide etc.), ahydroxide of an alkaline earth metal (e.g. barium hydroxide, calciumhydroxide etc.), or carbonate (e.g. sodium carbonate, potassiumcarbonate etc.), or an aqueous solution thereof, or a mixture thereof.

The (2) deprotection reaction under the acidic condition is performed,for example, at 0 to 100° C. in an organic solvent (e.g.dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropylalcohol, tetrahydrofuran, anisole etc.), in an organic acid (e.g. aceticacid, trifluoroacetic acid, methanesulfonic acid, p-tosylate etc.), oran inorganic acid (e.g. hydrochloric acid, sulfuric acid etc.) or amixture thereof (e.g. hydrogen bromide/acetic acid etc.), in thepresence or the absence of 2,2,2-trifluoroethanol.

The (3) deprotection reaction by hydrogenation degradation is performed,for example, at 0 to 200° C. in a solvent (e.g. ether-based solvent(e.g. tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether etc.),alcohol-based solvent (e.g. methanol, ethanol etc.), benzene-basedsolvent (e.g. benzene, toluene etc.), ketone-based solvent (e.g.acetone, methyl ethyl ketone etc.), nitrile-based solvent (e.g.acetonitrile etc.), amide-based solvent (e.g. N,N-dimethylformamideetc.), water, ethyl acetate, acetic acid, or a mixed solvent of two ormore of them etc.), in the presence of a catalyst (e.g.palladium-carbon, palladium black, palladium hydroxide-carbon, platinumoxide, Raney nickel etc.) under the hydrogen atmosphere at a normalpressure or under pressure, or in the presence of ammonium formate.

The (4) deprotection reaction of a silyl group is performed, forexample, at 0 to 40° C. in an organic solvent which is miscible withwater (e.g. tetrahydrofuran, acetonitrile etc.) using tetrabutylammoniumfluoride. Alternatively, the reaction is performed, for example, at −10to 100° C. in an organic acid (e.g. acetic acid, trifluoroacetic acid,methanesulfonic acid, p-tosylate etc.), or an inorganic acid (e.g.hydrochloric acid, sulfuric acid etc.) or a mixture thereof (e.g.hydrogen bromide/acetic acid etc.).

The (5) deprotection reaction using a metal is performed, for example,at 0 to 40° C. in an acidic solvent (e.g. acetic acid, a buffer of pH4.2 to 7.2, or a mixed solution of any of those solutions and an organicsolvent such as tetrahydrofuran etc.) in the presence of a zinc powder,if necessary, while an ultrasound is applied.

The (6) deprotection reaction using a metal complex is performed, forexample, at 0 to 40° C. in an organic solvent (e.g. dichloromethane,N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile,dioxane, ethanol etc.), water or a mixed solvent thereof, in thepresence of a trap reagent (e.g. tributyltin hydride, triethylsilane,dimedone, morpholine, diethylamine, pyrrolidine etc.), an organic acid(e.g. acetic acid, formic acid, 2-ethylhexanoic acid etc.) and/or anorganic acid salt (e.g. sodium 2-ethylhexanoate, potassium2-ethylhexanoate etc.), in the presence or the absence of aphosphine-based reagent (e.g. triphenylphosphine etc.), using a metalcomplex (e.g. tetrakistriphenylphosphinepalladium (0),bis(triphenylphosphine)palladium (II) dichloride, palladium (II)acetate, tris(triphenylphosphine)rhodium (I) chloride etc.).

Additionally, in addition to the above reactions, the deprotectionreaction can be performed, for example, by the method described in T. W.Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.

Examples of the protective group of a hydroxy group include a methylgroup, a trityl group, a methoxymethyl (MOM) group, a 1-ethoxyethyl (EE)group, a methoxyethoxymethyl (MEM) group, a 2-tetrahydropyranyl (THP)group, a trimethylsilyl (TMS) group, a triethylsilyl (TES) group, at-butyldimethylsilyl (TBDMS) group, a t-butyldiphenylsilyl (TBDPS)group, an acetyl (Ac) group, a pivaloyl group, a benzoyl group, ap-phenylbenzoyl group, a benzyl (Bn) group, a p-methoxybenzyl group, anallyloxycarbonyl (Alloc) group, a 2,2,2-trichloroethoxycarbonyl (Troc)group etc.

Examples of the protective group of an amino group include abenzyloxycarbonyl group, a t-butoxycarbonyl group, an allyloxycarbonyl(Alloc) group, a 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) group, atrifluoroacetyl group, a 9-fluorenylmethoxycarbonyl group, a benzyl (Bn)group, a p-methoxybenzyl group, a benzyloxymethyl (BOM) group, a2-(trimethylsilyl)ethoxymethyl(SEM) group etc.

The protective group of a hydroxy group is not particularly limited, asfar as it is a group which can be easily and selectively left, inaddition to the aforementioned protective groups. Protective groupsdescribed in, for example, T. W. Greene, Protective Groups in OrganicSynthesis, Wiley, New York, 1999 are used.

The compound represented by the general formula (II) can be produced bythe following reaction step formula 2.

(wherein T² represents a protective group of a hydroxy group (e.g.tert-butyldimethylsilyl (TBDMS) group etc.), X represents a halogen atomor COOR²⁻¹, R²⁻¹ represents the same meaning as that of R², R² and R²⁻¹may be the same or different, and other symbols represent the samemeanings as those described above)

In the reaction step formula 2, the compound represented by the generalformula (VII) can be produced by subjecting the compound represented bythe general formula (VI) to a protection reaction. For example, thereaction is performed at a temperature of −100 to 50° C. in an organicsolvent (e.g. DMF etc.) using a base (e.g. imidazole etc.) employing asilane compound (e.g. trimethylsilane chloride (TESCl),tert-butyldimethylsilane chloride (TBSCl), tert-butyldiphenylsilanechloride (TBDPSCl) etc.).

In the reaction step formula 2, the compound represented by the generalformula (VIII) can be produced by subjecting the compound represented bythe general formula (VII) to a reducing reaction. For example, thereaction is performed at −78 to 80° C. in an organic solvent (e.g.toluene, ethanol, tetrahydrofuran, hexane etc.) using a reducing agent(e.g. diisobutylaluminum hydride (DIBAL), lithium aluminum hydrideetc.).

In the reaction step formula 2, the reaction 3 is known, and isperformed, for example, at a temperature of −78 to 50° C. in an organicsolvent (e.g. anhydrous toluene, dimethoxyethane, tetrahydrofuran etc.)in the presence of a base (e.g. lithiumhexamethyldisilazane (LHMDS),lithiumdiisopropylamide (LDA), butyllithium, potassium tert-butoxide,sodium hydride etc.) using a Wittig reagent (e.g.methyltriphenylphosphonium bromide etc.).

In the reaction step formula 2, the reaction 4 is known, and isperformed, for example, at −50 to 120° C. in an organic solvent (e.g.tetrahydrofuran, DMF, DME, toluene etc.) using a base (e.g. sodiumhydride, potassium tert-butoxide, butyllithium, sodium hydroxide etc.)employing alkyl halide (e.g. ethyl 2-(bromomethyl)acrylate,2,3-dibromopropene etc.).

Herein, when X represents COOR²⁻¹ in the compound of the general formula(X), the objective compound can be produced by subjecting the compoundof the general formula (X) as it is to the reaction 6, without via thefollowing reaction 5.

In the reaction step formula 2, the reaction 5 is known, and isperformed, for example, at a temperature of room temperature to 120° C.in an organic solvent (e.g. toluene, THF, DMF etc.) in the presence of apalladium catalyst (e.g. bis(tri-tert-butylphosphine)palladium(Pd(P(t-Bu)₃)₂), tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄),bis(triphenylphosphine)palladium dichloride (PdCl₂(PPh₃)₂)etc.), usingan organozinc compound (e.g. a compound represented by the followinggeneral formula (X-1):

(wherein X¹ represents a halogen atom, and other symbols represent thesame meanings as those described above) etc.).

In the reaction step formula 2, the reaction 6 is known, and isperformed, for example, a temperature of 20 to 80° C. in an organicsolvent (e.g. toluene, dichloromethane, dichloroethane etc.) using ametathesis catalyst (e.g.2,6-diisopropylphenylimidoneophylidenemorbidenium (VI)bis(tert-butoxide), 2,6-diisopropylphenylimidoneophylidenemorbidenium(VI) bis(hexafluorotert-butoxide)etc.).

In the reaction step formula 2, the compound represented by the generalformula (XIII) can be produced by subjecting the compound represented bythe general formula (XII) to a hydrolysis reaction. For example, thereaction is performed at 0 to 80° C. in the presence of a hydroxide ofan alkali metal (e.g. sodium hydride, potassium hydride, lithium hydrideetc.) in a hydrous solvent (e.g. a mixed solvent of an alcohol-basedsolvent (e.g. methanol, ethanol, propanol, isopropyl alcohol etc.) andwater).

In the reaction step formula 2, the compound represented by the generalformula (XIV) can be produced by subjecting the compound represented bythe general formula (XIII) to an esterification reaction. Examples ofthe esterification reaction include:

(1) A method using halogenated alkyl,(2) A method using acid halide,(3) A method using a mixed acid anhydride,(4) A method using a condensing agent, etc.

To specifically explain a method using alkyl halide as one example, forexample, the method is performed by reacting carboxylic acid with alkylhalide at 0 to 150° C. in an organic solvent (e.g. acetonitrile,acetone, N,N-dimethylformamide, dimethyl sulfoxide, chloroform,dichloromethane, diethyl ether, tetrahydrofuran etc.) in the presence ofcarbonate (e.g. cesium carbonate, sodium carbonate, potassium carbonateetc.), an organic base (e.g. dimethylformamide, triethylamine,diisopropylethylamine etc,) or hydride of an alkyl metal (sodium hydrideetc.).

In the reaction step formula 2, the reaction 7 is known, and isperformed

(1) by a reaction at 0° C. to 80° C. under the atmospheric pressure or ahigh pressure using a metal catalyst (e.g. palladium carbon, platinumoxide, rhodium-alumina, Raney nickel, Wilkinson complex, rutheniumcatalyst, iridium catalyst etc.) in an organic solvent (e.g. methanol,ethanol, ethyl acetate, dichloromethane, dichloroethane, etc.) using,for example, a hydrogen gas, or(2) by a reaction at −40 to 80° C. using a reducing agent (e.g. sodiumborohydride etc.) in an organic solvent (e.g. methanol, ethanol, etc.)in the presence or the absence of cerium chloride etc. as an additive.

Among products obtained by the reaction 7, after a desired opticalisomer is fractionated by optical resolution by a conventional method(e.g. method using optical resolution column), if necessary, theaforementioned protection reaction is performed, thereby, the compoundrepresented by the general formula (XV) can be produced.

Among the reaction step formula 2, the compound represented by thegeneral formula (XVI) can be produced by subjecting the compoundrepresented by the general formula (XV) to the aforementioneddeprotection reaction.

In the reaction step formula 2, the compound represented by the generalformula (II) can be produced by subjecting the compound represented bythe general formula (XVI) to an oxidation reaction. Examples of theoxidation reaction include:

(1) A method using DMSO oxidation (e.g. Swern oxidation),(2) A method using a Dess-Martin Reagent,(3) A method using a TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl)reagent, etc.

To specifically explain the method using DMSO oxidation as one example,for example, the method is performed by reacting an alcohol compound inan organic solvent (e.g. chloroform, dichloromethane, ethyl acetateetc.) in the presence of an activating agent (e.g. oxalyl chloride,acetic acid anhydride, pyridine-sulfur trioxide complex etc.), and anoxidizing agent (e.g. dimethyl sulfoxide etc.) and, further, reactingtertiary amine (e.g. triethylamine, N,N-diisopropylethylamine,N-methylmorpholine, N-ethylpiperidine, diazabicyclo[5.4.0]undec-7-eneetc.) at −78 to 40° C.

In the reaction step formula 2, as the compound having a symbol:

[Chemical Formula 32]

a compound obtained by performing optical resolution by a conventionalmethod (e.g. method using optical resolution column) in advance, andfractionating a desired optical isomer may be used.

In each reaction in the present specification, the compound used as astarting raw material, and the compound represented by the generalformula (III) or the general formula (VI) are known, or can be easilyproduced by the known method.

In each reaction in the present specification, a reaction accompanyingheating can be performed using a water bath, an oil bath, a sand bath ora microwave, as is apparent to a person skilled in the art.

In each reaction in the present specification, a solid phase-supportedreagent supported on a high-molecular polymer (e.g. polystyrene,polyacrylamide, polypropylene, polyethylene glycol etc.) may beappropriately used.

In each reaction in the present specification, the reaction product canbe purified by a normal purification means, for example, a method suchas distillation under normal pressure or under reduced pressure, highperformance liquid chromatography using silica gel or magnesiumsilicate, thin layer chromatography, an ion-exchange resin, a scavengerresin, or column chromatography or washing, recrystallization etc.Purification may be performed for every reaction, or may be performedafter completion of some reactions.

[Toxicity]

The present invention compound has very low toxicity, has little, forexample, eye stimulating property (hyperemia, corneal clouding etc.),aqueous humor protein rise etc., and can be safely used as a medicament.

[Application to Medicament]

Since the present invention compound has selective FP agonist activity,based on its intraocular pressure lowering action, it is useful as anagent for preventing and/or treating an ocular disease, for example,glaucoma (acute closed-angle glaucoma, chronic closed-angle glaucoma,secondary closed-angle glaucoma, primary open-angle glaucoma, secondaryopen-angle glaucoma, congenital glaucoma, normal pressure glaucoma,aqueous hyperproduction glaucoma, etc.), ocular hypertension, macularedema, macular degeneration, retina and optic nerve tensile force rise,myopia, hyperopia, astigma, dry eye, amotio retinae, cataract, ocularpressure rise due to trauma or inflammation, ocular pressure rise due toa drug such as a steroid or a hormone agent, intraocular pressure riseafter operation etc.

In addition, since the present invention compound has FP agonistactivity, it is also useful as a labor inducer, an ecbolic, an oxytocic,a therapeutic agent for dysmenorrhea, a therapeutic agent forosteoporosis, a sunburn revulsant, a white hair preventing agent, a hairgrowth promoter, an eyelash extender, a therapeutic agent for Meniere'sdisease, a therapeutic agent for a labyrinthian disease etc.

The present invention compound may be administered as a joint use drug,by combining with other drug for:

1) complementing and/or potentiating the preventing and/or treatingeffect of the compound,2) improving dynamic state-absorption of the compound, decreasing adose, and/or3) alleviating side effect of the compound.

The joint use drug of the present invention compound and other drug maybe administered in a form of a compounding agent in which bothingredients are incorporated into one preparation, or may take a form ofadministration of separate preparations. When administered byformulating into separate preparations, administration by simultaneousadministration and time lag is included. In addition, in administrationof time lag, the present invention compound may be administered earlier,and other drug may be administered later, or other drug may beadministered earlier, and the present invention compound may beadministered later. Respective administration methods may be the same ordifferent.

By joint use drug, a disease on which the preventing and/or treatingeffect is exerted is not particularly limited, but the disease may be adisease on which the preventing and/or treating effect of the presetinvention compound is complemented and/or potentiated.

Examples of other drug for complementing and/or potentiating thepreventing and/or treating effect on glaucoma of the present inventioncompound include sympathetic nerve agonists (α₂ agonists: e.g.apraclonidine hydrochloride etc., β₂ agonist: e.g. dipivefrinehydrochloride etc.), parasympathetic nerve agonists (e.g. pilocarpinehydrochloride, carbachol, demecarium, echothiophate or distigminebromide etc.), sympathetic nerve suppressants (α₁ blocker: e.g.bunazosin hydrochloride etc., β blocker e.g. timolol maleate, befunololhydrochloride, carteolol hydrochloride, or betaxolol hydrochloride etc.,alp blocker, e.g. levobunolol hydrochloride, nipradilol etc.),prostaglandin drugs (e.g. isopropyl unoprostone, latanoprost,bimatoprost, travoprost, tafluprost, EP2 agonist, EP4 agonist or DPagonist etc.), carbonic anhydrase inhibitors (e.g. acetazolamide,diclofenamide, methazolamide, dorzolamide hydrochloride, or brinzolamideetc.), hyperosmotic agents (e.g. glycerin, preparation incorporatingglycerin and fructose, isosorbide, or D-mannitol etc.), ROCK (Rhokinase) inhibitors (e.g. Y-27632 etc.), NMDA antagonists etc.

In addition, the therapeutic agent for glaucoma to be combined with thepresent invention compound includes not only therapeutic agents whichhave been found out until now, but also therapeutic agents which will befound out from now on.

The present invention compound is usually administered systemically orlocally in an oral or parenteral form. Examples of the oral agentinclude liquid drugs for internal application (e.g. elixirs, syrups,pharmaceutically acceptable water agents, suspensions, emulsions), solidpreparations for internal application (e.g. tablets (includingsublingual tablets, orally disintegrating tablets), pills, capsules(including hard capsules, soft capsules, gelatin capsules,microcapsules), powders, granules, torches) etc. Examples of theparenteral agents include solutions (e.g. injectables (subcutaneousinjectables, intravenous injectables, intramuscular injectables,intraperitoneal injectables, infusions etc.), eye drops (e.g. aqueouseye drops (aqueous eye drops, aqueous suspensions eye drops, viscous eyedrops, solubilized eye drops etc.), nonaqueous eye drops (nonaqueous eyedrops, nonaqueous suspension eye drops etc.)) etc.), externalpreparations (e.g. ointment (ocular ointment etc.)), ear drops etc.These preparations may be release-controlled agents such asrapid-releasing preparations and sustained-release preparations. Thesepreparations can be produced by the known method, for example, themethod described in Japanese Pharmacopoeia etc.

Solutions for internal application as the oral agent are produced bydissolving, suspending or emulsifying an active ingredient in a diluentwhich is generally used (e.g. purified water, ethanol or a mixedsolution thereof etc.). Further, this solution may contain wettingagents, suspending agents, emulsifiers, sweeteners, flavors, aromaticagents, preservatives, buffers etc.

Solid preparations for internal application as the oral agent areformulated into preparations according to a conventional method bymixing an active ingredient with excipients (e.g. lactose, mannitol,glucose, microcrystalline cellulose, starch etc.), binders (e.g.hydroxypropylcellulose, polyvinylpyrrolidone, magnesiumaluminometasilicate etc.), disintegrating agents (e.g. cellulose calciumglycolate etc.), lubricants (e.g. magnesium stearate etc.), stabilizers,solubilizers (glutamic acid, aspartic acid etc.) etc. In addition, ifnecessary, preparations may be covered with coating agents (e.g. whitesugar, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulosephthalate etc.), or may be covered with two or more layers.

The external preparation as the parenteral agent is produced by theknown method, or formulation which is usually used. For example, theointment preparations are produced by kneading an active ingredient in abase or melting an active ingredient in a base. An ointment base isselected from bases which are known, or are usually used. For example,an ointment base selected from higher fatty acids or higher fatty acidesters (e.g. adipic acid, myristic acid, palmitic acid, stearic acid,oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester,stearic acid ester, oleic acid ester, etc.), waxes (e.g. beewax, whalewax, ceresin etc.), surfactants (e.g. polyloxyethylene alkyl etherphosphoric acid ester etc.), higher alcohols (e.g. cetanol, stearylalcohol, cetostearyl alcohol etc.), silicone oils (e.g.dimethylpolysiloxane etc.), hydrocarbons (e.g. hydrophilic vaseline,white vaseline, purified lanolin, liquid paraffin etc., glycols (e.g.ethylene glycol, diethylene glycol, propylene glycol, polyethyleneglycol, macrogol etc.), vegetable oils (e.g. castor oil, olive oil,sesame oil, turpentine oil etc.), animal oils (e.g. mink oil, yolk oil,squalane, squalene etc.), water, absorption promoter, and rashpreventing agents, alone, is used, or a mixture of two or more kinds isused. Further, the ointment base may contain humectants, preservatives,stabilizers, antioxidants, coloring agents etc.

The injectable as the parenteral agent includes solutions, suspensions,emulsions and solid injectables which are used by dissolving orsuspending a solid in a solvent upon use. The injectable is used, forexample, by dissolving, suspending or emulsifying an active ingredientin a solvent. As the solvent, for example, distilled water forinjection, physiological saline, vegetable oil, alcohols such aspropylene glycol, polyethylene glycol and ethanol etc., and acombination thereof are used. Further, this injectable may containstabilizers, solubilizers (e.g. glutamic acid, aspartic acid,polysorbate 80 (registered trademark) etc.), suspending agents,emulsifiers, soothing agents, buffers, preservatives etc. These areproduced by sterilization in a final step, or by a sterilizationoperation method. Alternatively, a sterile solid agent, for example, alyophilized product is produced, and it can be also used bysterilization before use thereof, or can be also used by dissolving theproduct in sterile distilled water for injection or other solvent.

Examples of a preferable dosage form of the present invention compoundinclude eye drops, ocular ointments, tablets etc., and more preferableis eye drops or ocular ointment. These can be formulated intopreparations using the generally used technique. For example, in thecase of eye drops, as additives, tonicity agents, buffers, pH adjustingagents, solubilizers, thickeners, stabilizers, preservatives etc. can beappropriately incorporated. Alternatively, stable eye drops can be alsoobtained by adding pH adjusting agents, thickeners, or dispersants, andsuspending drugs.

Examples of the tonicity agent include glycerin, propylene glycol,sodium chloride, potassium chloride, sorbitol, mannitol, etc.

Examples of the buffer include phosphoric acid, phosphate, citric acid,acetic acid, ε-aminocaproic acid etc.

Examples of the pH adjusting agent include hydrochloric acid, citricacid, phosphoric acid, acetic acid, sodium hydroxide, potassiumhydroxide, boric acid, borax, sodium carbonate, sodium bicarbonate etc.

Examples of the solubilizer include polysorbate 80, polyoxyethylenehardened castor oil 60, macrogol 4000 etc.

Examples of the thickener and dispersant include cellulose-basedpolymers such as hydroxypropylmethylcellulose andhydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone etc.,and examples of the stabilizer include edetic acid and sodium edetateetc.

Examples of the preservative (antiseptic agent) include general-usesorbic acid, potassium sorbate, benzalkonium chloride, benzethoniumchloride, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanoletc., and these preservatives can be also used by combining them.

In eye drops containing the active ingredient of the present invention,it is desirable that a pH is set at 4.0 to 8.5, and it is desirable thatan osmotic pressure ratio is set at around 1.0.

A dose of the active ingredient of the present invention can beappropriately selected depending on a symptom, an age, a dosage formetc. and, in the case of the oral agent, preferably 1 to 1000 mg, morepreferably 5 to 300 mg may be administered once to a few times (e.g.once to three times) per day. In the case of eye drops, one to a fewdrops having a concentration of preferably 0.000001 to 5% (w/v), morepreferably 0.00001 to 0.05% (w/v) as a one time amount may beadministered to eyes once to a few times (e.g. once to eight times) perday. In addition, in the case of the ocular ointment, an ocular ointmenthaving a concentration of preferably 0.000001 to 5% (w/w), morepreferably 0.00001 to 0.05% (w/w) may be coated once to a few times(e.g. once to four times) per day.

Of course, since a dose varies depending on a variety of conditions asdescribed above, an amount smaller than the aforementioned dose issufficient in some cases, or an amount exceeding the range is necessaryin some cases.

EXAMPLES

The present invention will be described in detail below by way ofExamples, but the present invention is not limited by them.

A solvent in a parenthesis shown in a place of separation bychromatography and TLC indicates an eluting solvent or a developingsolvent used, and a ratio represents a volumetric ratio.

NMR data is data of ¹H-NMR unless otherwise is indicated.

A solvent used in measurement is indicated in a parenthesis shown at aplace of NMR.

A compound name used in the present specification was generally named byusing a computer program, ACD/Name (registered trademark) of AdvancedChemistry Development, which performs naming according to a rule ofIUPAC, or according to IUPAC nomenclature.

Example 1: (3aR, 4S, 5R,6aS)-4-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one

To a dimethylformamide (hereinafter, abbreviated as DMF in some cases)(100 mL) solution of (3aR, 4S, 5R,6aS)-4-(hydroxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one(50 g) were sequentially added imidazole (29.22 g), andtert-butyldimethylchlorosilane (30.87 g) under ice-cooling, and themixture was stirred at room temperature for 3.5 hours. After completionof the reaction, a small amount of ethanol was added, the reactionsolution was poured into ice water, and this was extracted with ethylacetate:hexane (2:3). The extract was washed with 1N hydrochloric acid,an aqueous saturated sodium bicarbonate solution, water and a saturatedsaline, dried with sodium sulfate, and concentrated under reducedpressure to obtain a titled compound (76.2 g) having the followingphysical property values.

TLC: Rf 0.42 (hexane:ethyl acetate=3:1).

Example 2: (3aR, 4S, 5R,6aS)-4-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol

Under the argon atmosphere, an anhydrous toluene (390 mL) solution ofthe compound (76.2 g) produced in Example 1 was cooled to −70° C., a 1mol/L toluene solution (212.4 mL) of diisobutylaluminum hydride wasadded dropwise over about 1 hour, and mixture was stirred for 30 minuteas it was. After completion of the reaction, the reaction solution wasdiluted with tert-butyl methyl ether (hereinafter, abbreviated as MTBEin some cases) (400 mL), and an aqueous saturated sodium sulfatesolution was added. The precipitated white precipitate was filtered withCelite (trade name), and the solvent was concentrated under reducedpressured to obtain a titled compound (80.7 g) having the followingphysical property values.

TLC: Rf 0.30 (hexane:ethyl acetate=3:1).

Example 3: (1S, 2R, 3S,4R)-2-allyl-3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol

Under the argon atmosphere, a 1.6M tetrahydrofuran (hereinafter,abbreviated as THF in some cases) solution (500 mL) oflithiumhexamethyldisilazane was added dropwise to an anhydrous toluene(300 mL) suspension of methyltriphenylphosphonium bromide (326.6 g)under ice-cooling, and the mixture was stirred at room temperature for 1hour. The mixture was cooled to −70° C. again, an anhydrous toluene (400mL) solution of the compound (85.2 g) produced in Example 2 was addeddropwise over about 1.5 hours, and the mixture was stirred at roomtemperature for 2 hours. After completion of the reaction, an aqueousammonium chloride solution was added, followed by extraction with ethylacetate. The organic layer was washed with water and a saturated saline,and dried with sodium sulfate, and the solvent was concentrated underreduced pressure. The resulting residue was purified with a columnapparatus (Hiflash-SI, Size 5 L×4, hexane: ethylacetate=100:0→85:15→75:25) manufactured by Yamazen Corporation to obtaina titled compound (41.87 g) having the following physical propertyvalues.

TLC: Rf 0.57 (hexane:ethyl acetate=3:1).

Example 4: {[(1S, 2R, 3S,5R)-2-allyl-3-[(2-bromo-2-propen-1-yl)oxy]-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]methoxy}(dimethyl)(2-methyl-2-propanyl)silane

Under the argon atmosphere, 2,3-dibromopropene (8.4 mL, 81.0 mmol) wasplaced into a flask, and this was cooled to an inner temperature of 5°C. using ice water. Sodium hydride (2.16 g, 54.1 mmol) was placedtherein, and the mixture was stirred for 5 minutes. The compound (10 g,27 mmol) produced in Example 3 was added dropwise over 50 minutes, andthe mixture was stirred at room temperature for 2 hours. The reactionsolution was carefully poured into an aqueous saturated ammoniumchloride solution, and this was extracted with MTBE, washed with anaqueous saturated ammonium chloride solution, dried with anhydroussodium sulfate, and concentrated. Purification with silica gel columnchromatography (hexane:ethyl acetate=95:5-80:20) afforded a titledcompound (10.9 g) having the following physical property values.

TLC: Rf 0.72 hexane:ethyl acetate=9:1).

Example 5: Ethyl 5-({[(1S, 2R, 3S,4R)-2-allyl-3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]oxy}methyl)-5-hexanoate

Under the argon atmosphere, the compound (10.9 g, 22.2 mmol) produced inExample 4 was dissolved in toluene (100 mL), and 4-ethoxy-4-oxobutylzincbromide (0.5 mol/L THF solution, 133 mL, 66.7 mmol) was added at roomtemperature. Bis(tri-tert-butylphosphine)palladium (567 mg, 1.11 mmol)was added, and the mixture was stirred at 80° C. for 2 hours. This wascooled to room temperature, an aqueous saturated ammonium chloridesolution was added, and this was concentrated. The resulting residue wasdissolved in MTBE, and this was filtered using Celite (trade name). Thefiltrate was washed with an aqueous ammonium chloride solution, anaqueous saturated sodium bicarbonate solution, and a saturated saline,dried with magnesium sulfate, and concentrated. Purification with silicagel column chromatography (hexane:ethyl acetate=90:10-50:50) to obtain atitled compound (9.73 g) having the following physical property values.

TLC: Rf 0.65 (hexane:ethyl acetate=9:1).

Example 6: Ethyl 4-[(5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

Under the argon-atmosphere, the compound (400 mg, 0.762 mmol) producedin Example 5 was dissolved in toluene (76 mL). A Schrock's catalyst(2,6-diisopropylphenylimidoneophylidenemorbidenium (VI)bis(hexafluorotert-butoxide)) (785 mg, 0.925 mmol) was added to performa reaction at 85° C. for 18 hours. After allowing to cool, the reactionwas concentrated, and purified by silica gel column chromatography(hexane:ethyl acetate=90:10→50:50) to obtain a titled compound (4.8 mg)having the following physical property values.

TLC: Rf 0.47 (hexane:ethyl acetate=4:1).

Example 7: 4-[(5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl]butanoicacid

The compound (7.63 g, 15.4 mmol) produced in Example 6 was dissolved inethanol (60 mL), a 2.0 mol/L aqueous sodium hydroxide solution (20 mL)was added, and the mixture was stirred at room temperature for 2 hours.The reaction was concentrated, and ethyl acetate and 2 mol/Lhydrochloric acid were added, followed by extraction. The extract waswashed with a saturated saline, dried with anhydrous sodium sulfate, andconcentrated. The resulting titled compound was used in a next reactionwithout purification.

TLC: Rf 0.48 (chloroform:methanol=9.1)

Example 8: 2-Propanyl 4-[(5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

Under the argon atmosphere, the compound (15.4 mmol) produced in Example8 was dissolved in DMF, potassium carbonate (5.31 g, 38.5 mmol) andisopropyl iodide (2.31 mL, 23.1 mmol) were added, and the mixture wasstirred at 60° C. for 3 hours. After cooling, MTBE and water were added,and this was extracted, washed with a saturated saline, dried withanhydrous sodium sulfate, and concentrated. Purification by silica gelcolumn chromatography (hexane:ethyl acetate=90:10→50:50) afforded atitled compound (7.25 g) having the following physical property values.

TLC: Rf 0.90 (ethyl acetate).

Example 9: 2-Propanyl 4-[(5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

Under the argon atmosphere, a dichloromethane solution (62 mL) of thecompound (4.85 g, 9.45 mmol) produced in Example 8 was degassed using anultrasound, and argon replacement was performed. A Crabtree's catalyst(tricyclohexylphosphine) (1,5-cyclooctadiene) (pyridine)iridium (I)hexafluorophosphate) (760 mg, 0.945 mmol) was added, and the mixture wasstirred at room temperature for 3 hours and 50 minutes under thehydrogen atmosphere. The solution was concentrated under reducedpressure, and purified with a column apparatus (Hiflash-SI, Size 2 L,hexane→ethyl acetate:hexane=3:7) manufactured by Yamazen Corporation toobtain a titled compound (3.05 g) having the following physical propertyvalues.

TLC: Rf 0.72 (hexane:ethyl acetate=1:2).

Example 10 (1): 2-Propanyl 4-[(3S, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl]butanoateExample 10 (2): 2-Propanyl 4-[(3R, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

Under the argon atmosphere, a dichloromethane solution (60 mL) of thecompound (3.02 g, 5.89 mmol) produced in Example 9 was cooled to −20° C.A dimethylaluminum chloride solution (1.0M hexane solution) was added,and the mixture was stirred for 3 hours and 40 minutes while atemperature was raised to room temperature. The reaction solution waspoured into an ice-cooled aqueous saturated sodium bicarbonate solution,a Rochelle salt was added, and the mixture was stirred for 40 minutes.The aqueous layer was extracted with ethyl acetate two times, and thecollected organic layers were washed with a saturated saline, and driedwith anhydrous sodium sulfate. The solution was concentrated underreduced pressure, and purified with a column apparatus (Hiflash-SI, Size5 L, toluene:acetone=10:1) manufactured by Yamazen Corporation once, andwith (Hiflash-SI, Size 2 L+YAMAZEN ULTRA PACK SI-C, Size 37×300,toluene:acetone=10:1) two times to obtain a compound (1.60 g) of Example10 (1) and a compound (810 mg) of Example 10 (2) having the followingphysical property values.

TLC: Rf 0.30 (toluene:acetone=9:1) (compound of Example 10 (1));

TLC: Rf 0.31 (toluene:acetone=9:1) (compound of Example 10 (2)).

Example 11: 2-Propanyl 4-[(3S, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

Under the argon atmosphere, 3,4-dihydro-2H-pyran (403 μL, 4.42 mmol) andtosic acid monohydrate (10 mg, 0.111 mmol) were added to a toluenesolution (1.85 mL) of the compound (1.58 g, 3.69 mmol) produced inExample 10 (1), and the mixture was stirred at room temperature for 15minutes. Tosic acid monohydrate (10 mg, 0,111 mmol) was added, themixture was stirred for 45 minutes, triethylamine (100 μL) was added,and the reaction solution was concentrated under reduced pressure.Purification with a column apparatus (Hiflash-SI, Size 2 L, hexane→ethylacetate:hexane=3:7) manufactured by Yamazen Corporation to obtain atitled compound (1.82 g) having the following physical property values.

TLC: Rf 0.46 (hexane:ethyl acetate=1:1).

Example 12: 2-Propanyl 4-[(3S, 5aR, 6S, 7R,8aS)-6-(hydroxymethyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

Under the argon atmosphere, tetrabutylammonium fluoride (7 mL, 1.0M THFsolution) was added to a THF solution (3.6 mL) of the compound (1.81 g,3.53 mmol) produced in Example 11, and the mixture was stirred at roomtemperature for 70 minutes. Tetrabutylammonium fluoride (3.5 mL, 1.0mol/L THF solution) was added, and the mixture was further stirred at45° C. for 100 minutes. The reaction solution was diluted with ethylacetate (100 mL), washed with an aqueous saturated ammonium chloridesolution once, and with an aqueous saturated sodium chloride solutiononce, and dried with anhydrous sodium sulfate. The solution wasconcentrated under reduced pressure, and purified with column apparatus(Hiflash-SI, Size L, ethyl acetate:hexane=2:8→ethyl acetate:hexane=8:2)manufactured by Yamazen Corporation to obtain a titled compound (1.21 g)having the following physical property values.

TLC: Rf 0.40 (hexane:ethyl acetate=1:2).

Example 13: 2-Propanyl 4-[(3S, 5aR, 6R, 7R,8aS)-6-formyl-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

Under the argon-atmosphere, dimethyl sulfoxide (hereinafter, abbreviatedas DMSO in some cases) (1.8 mL) and diisopropylethylamine (1.8 mL, 10.56mmol) were added to an ethyl acetate solution (4 mL) of the compound(623 mg, 1.76 mmol) produced in Example 12, and the mixture was cooledto 0° C. A pyridine-sulfur trioxide complex (840 mg, 5.28 mmol) wasadded, and the mixture was stirred at 0° C. for 40 minutes. The reactionsolution was diluted with ethyl acetate, and poured into ice-cooledhydrochloric acid (0.5 N). The aqueous layer was extracted with ethylacetate once, and the collected organic layers were washed with anaqueous saturated sodium bicarbonate solution once, and with a saturatedsaline, and dried with anhydrous sodium sulfate. The solution wasconcentrated under reduced pressure to obtain a crude product (634 mg)of a titled compound having a following physical property values.

TLC: Rf 0.73 (hexane:ethyl acetate=2:1).

Example 14: 2-Propanyl 4-[(3S, 5aR, 6R, 7R,8aS)-6-[(1E)-3-oxo-4-phenoxy-1-buten-1-yl]-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

Under the argon atmosphere, dimethyl-(3-phenoxy-2-oxopropyl)-phosphonate(826 mg, 3.20 mmol) and potassium phosphate (679 mg, 3.20 mmol) wereadded to a THF solution (16 mL) of the compound (634 mg, 1.60 mmol)produced in Example 13, and the mixture was stirred at room temperaturefor one day. The reaction solution was added to an aqueous saturatedammonium chloride solution, and the aqueous layer was extracted withethyl acetate two times. The collected organic layers were washed with asaturated saline, and dried with anhydrous sodium sulfate. The solutionwas concentrated under reduced pressure, and purified with a columnapparatus (Hiflash-SI, Size L, hexane→ethyl acetate:hexane=4:6)manufactured by Yamazen Corporation to obtain a titled compound (426 mg)having the following physical property values.

TLC: Rf 0.55 (hexane:ethyl acetate=1:1).

Example 15: 2-Propanyl 4-[(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

(R)-2-methyl-CBS-oxazaborolidine (65 μL, 1 mol/L toluene solution, 0.065mmol) was added to a THF solution (16 mL) of the compound (137 mg, 0.259mmol) produced in Example 14. A borane dimethyl sulfide complex (155 μL,1 mol/L toluene solution, 0.155 mmol) was added dropwise. After stirredat room temperature for 45 minutes, the solution was diluted with ethylacetate, and poured into an aqueous saturated ammonium chloridesolution. The aqueous layer was extracted with ethyl acetate two times,and the collected organic layers were washed with a saturated saline,and dried with anhydrous sodium sulfate. The resulting solution wasconcentrated under reduced pressure to obtain a crude product (151 mg)of a titled compound having the following physical property values.

TLC: Rf 0.32 (hexane:ethyl acetate=2:1).

Example 16 (1): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

THF (400 μL) and water (400 μL) were added to an acetic acid solution(800 μL) of the compound (151 mg, 0.259 mmol) produced in Example 15,and the mixture was stirred at 60° C. for 3 hours and 30 minutes. Thereaction solution was concentrated under reduced pressure, and purifiedwith a column apparatus (Hiflash-SI, Size S, ethylacetate:hexane=1:1→ethyl acetate) manufactured by Yamazen Corporation toobtain a titled compound (74 mg) having the following physical propertyvalues. TLC: Rf 0.28 (dichloromethane:methanol=20:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.90-1.19, 1.22, 1.36-1.83, 1.84-1.96,2.03-2.18, 2.23, 2.41-2.53, 2.57, 2.84-2.97, 3.64-3.80, 3.83-3.91,3.92-4.09, 4.44-4.59, 4.88-5.09, 5.53-5.77, 6.83-7.04, 7.14-7.35.

Example 16 (2) to Example 16 (42)

Using (3 aR, 4S, 5R,6aS)-4-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one,using 4-ethoxy-4-oxobutylzinc bromide or a corresponding organozincreagent in place of it, and usingdimethyl-(3-phenoxy-2-oxopropyl)-sulfonate or a corresponding phosphonicacid salt in place of it, those substances were subjected to the sameobjective operations as those of Example 1→Example 2→Example 3→Example4→Example 5→Example 6→Example 7→Example 8→Example 9→Example 10 (1) orExample 10 (2)→Example 11→*Example 12→Example 13→Example 14→Example15→Example 16 (1) to obtain the following Example compounds.

Example 16 (2): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3S)-3-hydroxy-5-phenyl-1-penten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.41 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.87-1.19, 1.22, 1.34-1.98, 2.00-2.14, 2.23,2.39-2.54, 2.59-2.80, 2.84-2.97, 3.59-3.78, 3.88-4.23, 4.90-5.09,5.37-5.51, 5.53-5.65, 7.10-7.24, 7.23-7.38.

Example 16 (3): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.48 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.88-1.19, 1.22, 1.35-1.96, 2.02-2.16, 2.23,2.41-2.55, 2.56-2.69, 2.82-3.00, 3.63-3.79, 3.81-4.12, 4.42-4.55,4.89-5.08, 5.54-5.72, 6.77-6.84, 6.91-6.98, 7.20.

Example 16 (4): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(3-methylphenoxy)-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.45 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.89-1.29, 1.35-1.97, 2.01-2.17, 2.23,2.28-2.40, 2.42-2.54, 2.66-2.83, 2.83-2.97, 3.62-3.78, 3.78-4.12,4.40-4.56, 4.89-5.08, 5.54-5.73, 6.64-6.75, 6.78, 7.16.

Example 16 (5): Ethyl 4-{(3R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}benzoate

TLC: Rf 0.19 (hexane:ethyl acetate=1:2);

¹H-NMR (300 MHz, CDCl₃): δ 1.32-1.43, 1.50-1.81, 1.80-2.11, 2.11-2.28,2.41-2.60, 2.99, 3.28, 3.71-3.85, 3.84-3.94, 4.01, 4.05-4.18, 4.35,4.48-4.62, 5.60-5.80, 6.85-7.03, 7.16-7.36, 7.90-8.02.

Example 16 (6): Ethyl 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}benzoate

TLC: Rf 0.22 (hexane:ethyl acetate=1:2);

¹H-NMR (300 MHz, CDCl₃): δ 1.33-1.43, 1.46-1.96, 1.96-2.10, 2.11-2.43,2.43-2.58, 2.58-2.78, 2.93-3.13, 3.66-4.18, 4.25, 4.30-4.42, 4.49,5.54-5.77, 6.83-7.02, 7.17-7.33, 7.41-7.50, 7.92-8.01.

Example 16 (7): Ethyl 3-{(3R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}benzoate

TLC: Rf 0.56 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.39, 1.53-2.32, 2.43-2.66, 2.91-3.11, 3.30,3.69-3.84, 3.85-3.95, 3.97-4.05, 4.05-4.18, 4.37, 4.48-4.60, 5.60-5.79,6.84-7.04, 7.19-7.43, 7.80-7.93.

Example 16 (8): Ethyl 3-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}benzoate

TLC: Rf 0.59 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.34-1.43, 1.47-1.95, 1.95-2.12, 2.15-2.33,2.40-2.58, 2.66-3.19, 3.64-3.99, 4.02-4.14, 4.22, 4.30-4.42, 4.43-4.54,5.53-5.72, 6.81-7.00, 7.19-7.30, 7.32-7.42, 7.60-7.69, 7.84-7.92,7.94-8.01.

Example 16 (9): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(4-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.44 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.87-1.19, 1.22, 1.32-1.97, 2.01-2.17, 2.23,2.40-2.56, 2.70-2.99, 2.99-3.24, 3.59-3.77, 3.80-4.11, 4.38-4.56,4.88-5.08, 5.52-5.70, 6.75-6.91, 7.18-7.25.

Example 16 (10): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(4-methylphenoxy)-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.49 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.90-1.18, 1.22, 1.37-1.83, 1.83-1.95, 2.01,2.05-2.17, 2.23, 2.29, 2.40-2.56, 2.84-2.97, 3.66-3.79, 3.84, 3.90-4.09,4.50, 4.91-5.07, 5.57-5.73, 6.76-6.85, 7.03-7.12.

Example 16 (11): 2-Propanyl 4-[(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-{(1E,3R)-3-hydroxy-4-[4-(trifluoromethyl)phenoxy]-1-buten-1-yl}octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

TLC: Rf 0.47 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.90-1.19, 1.21, 1.36-1.96, 2.06-2.29,2.41-2.68, 2.91, 3.66-3.79, 3.88-4.10, 4.48-4.60, 4.90-5.08, 5.57-5.76,6.97, 7.54.

Example 16 (12): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.53 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.85-1.19, 1.22, 1.34-1.96, 2.03-2.18,2.18-2.29, 2.39-2.57, 2.71-2.84, 2.84-2.99, 3.63-3.80, 3.85-4.13,4.47-4.61, 4.88-5.09, 5.55-5.77, 6.84-7.15.

Example 16 (13): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.55 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.91-1.19, 1.22, 1.34-1.97, 1.99-2.20, 2.23,2.37-2.60, 2.91, 3.65-3.79, 3.81-4.12, 4.45-4.60, 4.91-5.10, 5.56-5.75,6.59-6.74, 7.11-7.32.

Example 16 (14): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(4-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.55 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.90-1.18, 1.22, 1.36-1.98, 1.99-2.18, 2.23,2.40-2.68, 2.84-2.97, 3.64-3.79, 3.79-3.89, 3.89-4.14, 4.44-4.57,4.89-5.11, 5.56-5.75, 6.80-6.91, 6.91-7.03.

Example 16 (15): 2-Propanyl 4-[(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-{(1E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-buten-1-yl}octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

TLC: Rf 0.46 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.90-1.19, 1.19-1.25, 1.36-1.97, 2.00-2.19,2.23, 2.41-2.56, 2.85-2.98, 3.67-3.80, 3.88-4.09, 4.48-4.60, 4.91-5.08,5.59-5.76, 7.09, 7.12-7.17, 7.21-7.25, 7.40.

Example 16 (16): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(3-methoxyphenoxy)-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.43 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.89-1.18, 1.81-1.26, 1.35-1.97, 2.02-2.19,2.23, 2.40-2.60, 2.83-2.98, 3.63-4.10, 4.45-4.58, 4.89-5.08, 5.56-5.74,6.43-6.58, 7.17.

Example 16 (17): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(4-methoxyphenoxy)-1-buten-1-yl]octahydro-2H-cyclopenta[b]xepin-3-yl}butanoate

TLC: Rf 0.44 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.89-1.18, 1.23, 1.35-1.96, 2.04-2.29,2.40-2.55, 2.61, 2.84-2.97, 3.64-3.87, 3.89-4.09, 4.43-4.55, 4.91-5.06,5.56-5.73, 6.75-6.92.

Example 16 (18): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(2-methylphenoxy)-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.50 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.85-1.19, 1.19-1.26, 1.33-1.97, 1.98-2.18,2.18-2.30, 2.38-2.59, 2.82-3.00, 3.62-3.81, 3.83-4.14, 4.46-4.64,4.88-5.09, 5.56-5.78, 6.77-6.84, 6.84-6.94, 7.05-7.21.

Example 16 (19): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.48 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.87-1.18, 1.22, 1.35-1.95, 1.99-2.18, 2.23,2.40-2.54, 2.62-2.74, 2.91, 3.65-3.80, 3.88-3.99, 3.99-4.11, 4.49-4.65,4.89-5.08, 5.57-5.76, 6.86-6.98, 7.15-7.24, 7.30-7.40.

Example 16 (20): 2-Propanyl 6-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}hexanoate

TLC: Rf 0.59 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.88-1.17, 1.18-1.37, 1.40-1.94, 1.98-2.19,2.20-2.30, 2.36-2.56, 2.89, 3.66-4.10, 4.46-4.59, 4.91-5.07, 5.57-5.75,6.87-7.01, 7.24-7.33.

Example 16 (21): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3,5-dichlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.57 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.87-1.19, 1.17-1.25, 1.33-1.83, 1.82-1.98,2.00-2.19, 2.23, 2.38-2.59, 2.82-2.97, 3.63-3.79, 3.80-4.16, 4.40-4.61,4.88-5.10, 5.52-5.75, 6.81, 6.97.

Example 16 (22): 2-Propanyl 4-[(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chloro-5-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

TLC: Rf 0.56 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.87-1.17, 1.81-1.25, 1.34-1.83, 1.83-1.97,2.04-2.18, 2.23, 2.40-2.55, 2.84-2.97, 3.64-3.79, 3.82-3.90, 3.91-3.99,3.99-4.13, 4.41-4.59, 4.90-5.09, 5.53-5.74, 6.48-6.59, 6.65-6.79.

Example 16 (23): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,3-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.51 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.88-1.18, 1.18-1.26, 1.34-1.81, 1.82-1.99,2.04-2.16, 2.18-2.28, 2.37-2.56, 2.73, 2.91, 3.63-3.80, 3.87-4.15,4.46-4.65, 4.86-5.07, 5.53-5.77, 6.67-6.85, 6.89-7.07.

Example 16 (24): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.54 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.87-1.18, 1.18-1.25, 1.36-1.84, 1.82-1.97,2.03-2.19, 2.23, 2.40-2.58, 2.83-2.99, 3.65-3.80, 3.81-3.90, 3.90-4.12,4.41-4.59, 4.87-5.11, 5.52-5.79, 6.32-6.54.

Example 16 (25): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.54 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.92-1.18, 1.21, 1.34-1.82, 1.82-1.96,2.03-2.18, 2.23, 2.28, 2.41-2.54, 2.78, 2.84-2.98, 3.62-3.80, 3.86-4.11,4.47-4.61, 4.89-5.07, 5.54-5.76, 6.54-6.66, 6.66-6.76, 6.93-7.05.

Example 16 (26): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(5-chloro-2-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.69 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.90-1.19, 1.22, 1.37-1.96, 2.03-2.29,2.41-2.54, 2.68, 2.91, 3.65-3.80, 3.86-4.11, 4.48-4.60, 4.91-5.08,5.55-5.75, 6.86-6.94, 6.94-7.06.

Example 16 (27): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chloro-4-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.58 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.91-1.19, 1.21, 1.37-1.97, 2.02-2.19, 2.23,2.41-2.54, 2.91, 3.66-3.80, 3.80-3.89, 3.89-4.10, 4.45-4.56, 4.99,5.55-5.75, 6.73-6.81, 6.95, 7.00-7.10.

Example 16 (28): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]-7-methoxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.72 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.88-1.19, 1.22, 1.36-1.81, 1.81-1.97,2.15-2.29, 2.42, 2.46-2.59, 2.91, 3.25-3.47, 3.81-4.09, 4.46-4.59,4.89-5.10, 5.56-5.67, 5.69-5.82, 6.87-7.02, 7.23-7.35.

Example 16 (29): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chloro-2-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.37 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.84-1.18, 1.19-1.27, 1.34-1.97, 2.02-2.19,2.23, 2.39-2.54, 2.66, 2.81-2.99, 3.61-3.82, 3.86-4.12, 4.45-4.63,4.88-5.09, 5.55-5.76, 6.82-6.91, 6.93-7.07.

Example 16 (30): 2-Propanyl {(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}acetate

TLC: Rf 0.43 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.02-1.19, 1.22, 1.42-1.59, 1.63-1.96,2.02-2.28, 2.41-2.55, 2.60, 2.92-3.04, 3.65-3.79, 3.82-3.92, 3.92-4.12,4.44-4.58, 4.89-5.08, 5.55-5.75, 6.80, 6.91, 6.95, 7.19.

Example 16 (31): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,4-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.63 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.89-1.18, 1.18-1.25, 1.35-1.82, 1.82-1.94,2.03-2.16, 2.23, 2.40-2.56, 2.84-2.95, 2.97, 3.70, 3.85-4.08, 4.46-4.55,4.92-5.06, 5.55-5.71, 6.73-6.98.

Example 16 (32): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3,4-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.62 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.91-1.18, 1.22, 1.36-1.83, 1.83-1.96,2.05-2.18, 2.23, 2.48, 2.53-2.59, 2.85-2.96, 3.65-3.78, 3.79-3.87,3.89-4.09, 4.44-4.55, 4.91-5.07, 5.56-5.73, 6.57-6.64, 6.73, 6.99-7.12.

Example 16 (33): 2-Propanyl 4-{(3R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.28 (dichloromethane:methanol=20:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.22, 1.34-1.98, 2.07-2.19, 2.21-2.33, 2.40,2.77, 3.02, 3.40, 3.65-3.77, 3.78-4.03, 4.44-4.56, 4.92-5.08, 5.57-5.71,6.87-7.01, 7.24-7.34.

Example 16 (34): Ethyl 4-{(3R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.25 (dichloromethane:methanol=20:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.25, 1.35-1.88, 2.08-2.23, 2.22-2.49, 2.67,3.41, 3.64-4.06, 4.12, 4.46-4.59, 5.58-5.78, 6.85-7.06, 7.22-7.37.

Example 16 (35): Ethyl 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.23 (dichloromethane:methanol=20:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.89-1.20, 1.25, 1.35-1.99, 2.03-2.19, 2.26,2.41-2.54, 2.58, 2.91, 3.65-3.81, 3.83-4.08, 4.12, 4.46-4.61, 5.58-5.75,6.84-7.05, 7.22-7.37.

Example 16 (36): 2-Propanyl 4-{(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.47 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.23, 1.34-1.89, 2.07-2.22, 2.27, 2.34-2.46,2.47-2.67, 3.41, 3.67-4.06, 4.43-4.60, 4.91-5.10, 5.54-5.77, 6.78-6.84,6.92, 6.93-6.99, 7.20.

Example 16 (37): 2-Propanyl 4-{(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3S)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.47 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.23, 1.33-1.87, 1.86-1.96, 2.10-2.23,2.23-2.50, 3.42, 3.68-3.90, 3.93-4.07, 4.44-4.63, 4.91-5.10, 5.56-5.79,6.77-6.85, 6.92, 6.93-7.00, 7.20.

Example 16 (38): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3S)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.65 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.66-2.01, 2.04-2.18, 2.23, 2.29-2.57, 2.91,3.73, 3.85, 3.90-4.13, 4.45-4.59, 4.90-5.07, 5.53-5.78, 6.75-6.84, 6.91,6.92-6.98, 7.19.

Example 16 (39): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3S)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.39 (isopropyl alcohol:hexane=1:5);

¹H-NMR (300 MHz, CDCl₃): δ 0.91-1.18, 1.18-1.26, 1.36-1.83, 1.83-1.97,2.05-2.19, 2.23, 2.39-2.56, 2.91, 3.63-3.81, 3.82-4.11, 4.48-4.64,4.88-5.08, 5.54-5.77, 6.53-6.65, 6.66-6.79, 6.93-7.09.

Example 16 (40): 2-Propanyl {(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}acetate

TLC: Rf 0.59 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.02-1.18, 1.19-1.26, 2.10-2.39, 2.50,2.76-2.89, 3.00, 3.67-3.80, 3.88-4.13, 4.50-4.61, 5.00, 5.58-5.75, 6.62,6.72, 7.03.

Example 16 (41): 2-Propanyl 4-{(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.55 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.15-1.34, 1.35-1.87, 2.11-2.25, 2.29, 2.42,2.69, 3.43, 3.70-4.09, 4.51-4.62, 4.95-5.09, 5.58-5.76, 6.62, 6.73,7.03.

Example 16 (42): 2-Propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(cyclohexyloxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.33 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.91-1.35, 1.42-1.76, 1.85-1.93, 2.04-2.12,2.22-2.27, 2.42-2.51, 2.67, 2.87-2.95, 3.26-3.32, 3.50-3.55, 3.66-3.75,3.93-4.07, 4.24-4.29, 4.96-5.05, 5.50-5.64.

Example 17 (1): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,3-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

An aqueous sodium hydroxide solution (500 μL) was added to a methanolsolution (1.5 mL) of the compound (49 mg, 0.102 mmol) produced inExample 16 (23), and the mixture was stirred at 40° C. for 2 hours. Anice was placed into the reaction solution, and 1N hydrochloric acid (1.2mL) was added. This was extracted with ethyl acetate two times, and thecollected organic layers were washed with a saturated saline, and driedwith anhydrous sodium sulfate. The solution was concentrated underreduced pressure, and purified with a silica gel column (BW-235,dichloromethane:methanol=10:1) to obtain a titled compound (45 mg)having the following physical property values.

TLC: Rf 0.56 (ethyl acetate:methanol=8:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.78-1.24, 1.24-2.08, 2.25, 2.36-2.49,2.91-3.02, 3.59-3.73, 3.86-4.07, 4.38-4.49, 5.54-5.71, 6.75-6.86,6.86-6.94, 6.98-7.10.

Example 17 (2) to Example 17 (33)

Compounds produced in Example 16 (1) to Example 16 (22) and Example 16(24) to Example 16 (33) were subjected to the same objective operationsas those of Example 17 (1) to obtain the following Example compounds.

Example 17 (2): 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3S)-3-hydroxy-5-phenyl-1-penten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.38 (dichloromethane:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87-1.23, 1.32-1.97, 2.00-2.13, 2.32,2.40-2.54, 2.57-2.78, 2.91, 3.61-3.75, 3.85-4.20, 5.36-5.48, 5.52-5.66,7.11-7.33.

Example 17 (3): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.43 (dichloromethane:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.83-1.27, 1.35-1.97, 2.02-2.20, 2.33,2.41-2.55, 2.84-2.99, 3.67-3.78, 3.80-4.11, 4.45-4.58, 5.54-5.74,6.76-6.84, 6.91-6.98, 7.20.

Example 17 (4): 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(3-methylphenoxy)-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.46 (dichloromethane:methanol=6:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.80-1.21, 1.35-1.97, 2.00-2.19, 2.24-2.38,2.40-2.55, 2.91, 3.65-3.78, 3.82-3.90, 3.90-4.08, 4.45-4.57, 5.54-5.73,6.65-6.75, 6.78, 7.16.

Example 17 (5): 4-{(3R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}benzoicacid

TLC: Rf 0.36 (chloroform:methanol=9:1);

¹H-NMR (300 MHz, CD₃OD): δ 1.46-2.17, 2.40-2.56, 2.87-3.03, 3.33-3.45,3.63-3.77, 3.83-4.23, 4.35-4.49, 5.58-5.76, 6.82-6.99, 7.16-7.37, 7.92.

Example 17 (6): 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}benzoicacid

TLC: Rf 0.34 (chloroform:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.47-1.96, 1.95-2.12, 2.16-2.36, 2.44-2.61,2.97-3.15, 3.67-4.18, 4.28, 4.45-4.61, 5.56-5.75, 6.85-7.02, 7.22-7.34,7.46-7.54, 7.99-8.07.

Example 17 (7): 3-{(3R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}benzoicacid

TLC: Rf 0.45 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 1.49-2.20, 2.41-2.56, 2.86-3.03, 3.32-3.44,3.63-3.78, 3.85-4.22, 4.37-4.49, 5.58-5.75, 6.84-6.98, 7.17-7.30,7.33-7.48, 7.79-7.89.

Example 17 (8): 3-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}benzoicacid

TLC: Rf 0.45 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CDCl₃): δ 1.48-1.72, 1.73-1.94, 1.95-2.13, 2.21-2.37,2.43-2.59, 3.00-3.15, 3.66-4.00, 4.03-4.14, 4.25, 4.44-4.56, 5.56-5.74,6.82-6.99, 7.19-7.30, 7.39, 7.65, 7.94, 8.11.

Example 17 (9): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(4-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.40 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 0.93-1.26, 1.26-1.82, 1.82-2.07, 2.25,2.36-2.50, 2.90-3.03, 3.59-3.71, 3.83-4.05, 4.35-4.45, 5.55-5.70,6.87-6.95, 7.19-7.28.

Example 17 (10): 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(4-methylphenoxy)-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.40 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 0.90-2.08, 2.18-2.33, 2.34-2.51, 2.97,3.58-3.73, 3.79-4.07, 4.31-4.47, 5.54-5.71, 6.73-6.86, 7.04.

Example 17 (11): 4-[(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-{(1E,3R)-3-hydroxy-4-[4-(trifluoromethyl)phenoxy]-1-buten-1-yl}octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoicacid

TLC: Rf 0.40 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 0.92-1.94, 1.94-2.08, 2.25, 2.36-2.50,2.91-3.03, 3.59-3.73, 3.91-4.07, 4.40-4.49, 5.57-5.72, 7.01-7.13,7.49-7.61.

Example 17 (12): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.39 (dichloromethane:methanol=10:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.78-2.10, 2.25, 2.35-2.49, 2.89-3.02,3.58-3.74, 3.90-4.06, 4.34-4.51, 5.53-5.72, 6.83-6.96, 7.01-7.15.

Example 17 (13): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.37 (dichloromethane:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.80-1.22, 1.34-1.97, 2.05-2.18, 2.32,2.40-5.56, 2.84-2.98, 3.66-3.78, 3.80-4.10, 4.46-4.57, 5.55-5.74,6.55-6.75, 7.14-7.28.

Example 17 (14): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(4-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.40 (dichloromethane:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.83-1.21, 1.34-1.98, 2.05-2.18, 2.32,2.39-2.57, 2.85-3.00, 3.66-3.79, 3.79-3.88, 3.89-4.09, 4.41-4.60,5.54-5.76, 6.79-6.91, 6.90-7.03.

Example 17 (15): 4-[(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-{(1E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-buten-1-yl}octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoicacid

TLC: Rf 0.37 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 0.92-2.09, 2.25, 2.37-2.50, 2.88-3.04,3.57-3.74, 3.89-4.07, 4.37-4.49, 5.54-5.74, 7.13-7.27, 7.38-7.51.

Example 17 (16): 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(3-methoxyphenoxy)-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.37 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 0.91-1.21, 1.27-1.83, 1.82-2.08, 2.25,2.36-2.50, 2.90-3.03, 3.59-3.72, 3.75, 3.80-4.05, 4.34-4.45, 5.55-5.70,6.44-6.55, 7.08-7.18.

Example 17 (17): 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(4-methoxyphenoxy)-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.39 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 0.93-1.24, 1.30-1.47, 1.47-1.82, 1.82-2.09,2.25, 2.36-2.50, 2.90-3.03, 3.59-3.71, 3.73, 3.78-3.92, 3.93-4.05,4.32-4.42, 5.54-5.70, 6.74-6.92.

Example 17 (18): 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(2-methylphenoxy)-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.61 (ethyl acetate:methanol=8:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.87-1.23, 1.24-1.93, 1.94-2.09, 2.15-2.32,2.35-2.50, 2.89-3.03, 3.58-3.72, 3.85-4.07, 4.37-4.47, 5.56-5.71,6.74-6.88, 7.03-7.15.

Example 17 (19): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.50 (ethyl acetate:methanol=8:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.84-1.21, 1.22-1.93, 1.93-2.10, 2.25,2.35-2.49, 2.96, 3.57-3.72, 3.89-4.06, 4.39-4.49, 5.57-5.71, 6.90, 7.05,7.19-7.27, 7.33.

Example 17 (20): 6-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}hexanoicacid

TLC: Rf 0.24 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 0.90-1.20, 1.22-1.47, 1.46-1.67, 1.66-1.93,1.93-2.08, 2.21-2.32, 2.36-2.49, 2.95, 3.59-3.72, 3.83-4.07, 4.35-4.47,5.55-5.71, 6.86-6.95, 7.19-7.30.

Example 17 (21): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3,5-dichlorophenoxy)-3-hydroxy-1-buten-1l-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.62 (ethyl acetate:methanol=8:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.90-1.22, 1.25-2.09, 2.25, 2.35-2.51, 2.97,3.58-3.72, 3.83-4.08, 4.31-4.48, 5.50-5.73, 6.93, 6.98.

Example 17 (22): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chloro-5-fluorophenoxy)-3-hydroxy-1-buten-1l-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.62 (ethyl acetate:methanol=8:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.90-1.22, 1.27-2.10, 2.26, 2.37-2.51, 2.97,3.58-3.73, 3.85-4.06, 4.35-4.47, 5.54-5.72, 6.69, 6.75, 6.79-6.85.

Example 17 (23): 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.33 (chloroform:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.90-1.30, 1.37-1.81, 1.82-1.96, 2.04-2.19,2.32, 2.41-2.54, 2.85-2.98, 3.65-3.79, 3.84-4.10, 4.47-4.58, 5.57-5.74,6.86-7.03, 7.23-7.35.

Example 17 (24): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.59 (ethyl acetate:methanol=8:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.91-1.24, 1.24-2.11, 2.25, 2.35-2.51, 2.97,3.57-3.75, 3.80-4.11, 4.29-4.50, 5.50-5.77, 6.38-6.68.

Example 17 (25): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.60 (ethyl acetate:methanol=8:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.89-1.23, 1.25-1.94, 1.95-2.10, 2.25,2.35-2.51, 2.92-3.03, 3.58-3.73, 3.87-4.09, 4.35-4.50, 5.55-5.75,6.58-6.71, 6.84-6.97, 6.99-7.14.

Example 17 (26): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(5-chloro-2-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.59 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 0.92-1.20, 1.29-1.46, 1.46-2.08, 2.25,2.36-2.49, 2.91-3.02, 3.59-3.71, 3.92-4.05, 4.38-4.47, 5.55-5.71,6.88-6.94, 7.07, 7.13.

Example 17 (27): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chloro-4-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.58 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 0.92-1.22, 1.30-1.47, 1.47-1.83, 1.82-2.07,2.25, 2.36-2.49, 2.90-3.03, 3.59-3.72, 3.82-4.05, 4.35-4.44, 5.54-5.70,6.84-6.92, 7.04, 7.13.

Example 17 (28): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]-7-methoxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.43 (chloroform:methanol:water=10:1:0.1);

¹H-NMR (300 MHz, CDCl₃): δ 0.89-1.22, 1.35-1.81, 1.81-1.97, 2.15-2.28,2.32, 2.46-2.59, 2.92, 3.26-3.46, 3.82-4.09, 4.48-4.58, 5.55-5.67,5.69-5.82, 6.87-7.02, 7.24-7.34.

Example 17 (29): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chloro-2-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.26 (dichloromethane:methanol=5:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.89-1.23, 1.25-2.06, 2.25, 2.31-2.51,2.87-3.03, 3.57-3.75, 3.87-4.09, 4.35-4.50, 5.52-5.73, 6.89-7.15.

Example 17 (30): {(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}aceticacid

TLC: Rf 0.26 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 1.04-1.20, 1.35-1.63, 1.65-2.19, 2.37-2.50,2.97-3.09, 3.25-3.38, 3.59-3.72, 3.85-4.07, 4.35-4.46, 5.55-5.70, 6.86,6.89-6.97, 7.22.

Example 17 (31): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,4-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.22 (chloroform:methanol:water=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 0.87-1.26, 1.26-1.82, 1.81-1.94, 1.94-2.07,2.25, 2.43, 2.97, 3.65, 3.91-4.06, 4.36-4.47, 5.54-5.71, 6.79-6.89,6.95, 7.09.

Example 17 (32): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3,4-difluorophenoxy)-3-hydroxy-1-buten-1l-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.22 (chloroform:methanol:water=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 0.93-1.24, 1.27-1.83, 1.82-1.94, 1.94-2.07,2.25, 2.43, 2.97, 3.65, 3.81-4.06, 4.35-4.44, 5.54-5.71, 6.67-6.76,6.86, 7.13.

Example 17 (33): 4-{(5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid (low polar body)

TLC: Rf 0.40 (chloroform:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.12-1.91, 2.07-2.91, 3.34-3.50, 3.65-4.06,4.46-4.58, 5.56-5.73, 6.84-7.05, 7.22-7.35.

Example 17 (34): 4-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3S)-3-hydroxy-1-octen-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

Using (3aR, 4S, 5R,6aS)-4-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one,using 4-ethoxy-4-oxobutylzinc bromide, and using a correspondingphosphonic acid salt in place ofdimethyl-(3-phenoxy-2-oxopropyl)-phosphonate, the substances weresubjected to the same objective operations as those of Example 1→Example2→Example 3→Example 4→Example 5→Example 6→Example 7→Example 8→Example9→Example 10→Example 11→Example 12→Example 13→Example 14→Example15→Example 16 (1)→Example 17 (1) to obtain a titled compound having thefollowing physical property values.

TLC: Rf 0.53 (ethyl acetate:methanol=8:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.77-1.21, 1.22-1.82, 1.82-2.05, 2.25,2.35-2.48, 2.91-3.02, 3.56-3.69, 3.88-4.07, 5.34-5.56.

Example 17 (35) to Example 17 (41)

Using the compounds produced in Example 16 (36) to Example 16 (42),these compounds were subjected to the same objective operations as thoseof Example 17 (1) to obtain the following Example compounds.

Example 17 (35): 4-{(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.64 (dichloromethane:methanol=5:1);

¹H-NMR (300 MHz, CD₃OD): δ 1.36-1.86, 1.97-2.12, 2.29, 2.33-2.45, 3.45,3.61-3.73, 3.77-3.85, 3.85-4.05, 4.34-4.47, 5.55-5.71, 6.83-6.89,6.89-6.94, 6.94-6.97, 7.22.

Example 17 (36): 4-{(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3S)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.63 (dichloromethane:methanol=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.37-1.88, 1.94-2.13, 2.29, 2.33-2.46, 3.45,3.60-3.74, 3.76-3.93, 3.94-4.06, 4.36-4.47, 5.57-5.72, 6.84-6.89,6.89-6.94, 6.96, 7.22.

Example 17 (37): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3S)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.58 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.76-2.13, 2.25, 2.35-2.50, 2.90-3.03,3.60-3.73, 3.82-3.92, 3.92-4.06, 4.35-4.49, 5.55-5.73, 6.83-6.89,6.86-6.94, 6.96, 7.22.

Example 17 (38): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3S)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.44 (dichloromethane:methanol=10:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.90-1.71, 1.71-1.86, 1.84-2.11, 2.25,2.34-2.52, 2.90-3.03, 3.56-3.75, 3.85-4.14, 4.37-4.56, 5.51-5.78,6.49-6.73, 6.82-7.00, 7.00-7.18.

Example 17 (39): {(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}aceticacid

TLC: Rf 0.50 (dichloromethane:methanol=5:1);

¹H-NMR (300 MHz, CD₃OD): δ 1.01-1.21, 1.33-1.62, 1.66-1.95, 1.95-2.18,2.44, 2.94-3.12, 3.66, 3.94-4.08, 4.40-4.48, 5.57-5.72, 6.63, 6.92,7.07.

Example 17 (40): 4-{(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.49 (dichloromethane:methanol=7:1);

¹H-NMR (300 MHz, CD₃OD): δ 1.38-1.86, 1.98-2.13, 2.29, 2.38, 3.46, 3.68,3.76-3.87, 3.95-4.06, 4.40-4.49, 5.57-5.72, 6.63, 6.93, 7.08.

Example 17 (41): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(cyclohexyloxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.81 (dichloromethane:methanol=4:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.95-1.90, 2.05-2.15, 2.32-2.37, 2.43-2.52,2.89-2.97, 3.27-3.33, 3.51-3.55, 3.66-3.75, 3.93-4.08, 4.25-4.31,5.50-5.64.

Example 17 (42) to Example 17 (45)

Using (3aR, 4S, 5R,6aS)-4-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one,using 4-ethoxy-4-oxobutylzinc bromide or a corresponding organozincreagent in place of it, and usingdimethyl-(3-phenoxy-2-oxopropyl)-phosphonate or a correspondingphosphonic acid salt in place of it, the compounds produced using themethods described in items of Example 16 (2) to Example 16 (42) weresubjected to the same objective operations as those of Example 17 (1) toobtain the following Example compounds.

Example 17 (42): 4-[(3S, 5aR, 6R, 7R, 8aS)-6-{(1E,3R)-4-[2-fluoro-5-(trifluoromethyl)phenoxy]-3-hydroxy-1-buten-1-yl}-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl]butanoicacid

TLC: Rf 0.38 (ethyl acetate:methanol=9:1);

¹H-NMR (300 MHz, DMSO-d₆): δ 11.97, 7.52-7.39, 7.31, 5.55, 5.48, 5.16,4.60, 4.30, 4.04-4.00, 3.90-3.81, 3.48, 2.83, 2.27, 2.15, 1.89-1.70,1.66-1.18, 1.11-0.83.

Example 17 (43): 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,6-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.36 (ethyl acetate:methanol=9:1);

¹H-NMR (300 MHz, DMSO-d₆): δ 11.97, 7.12-7.07, 5.54, 5.47, 5.07, 4.60,4.23, 3.97-3.82, 3.48, 2.83, 2.27, 2.15, 1.88-1.72, 1.65-1.20,1.07-0.85.

Example 17 (44): 4-[(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-{(1E,3R)-3-hydroxy-4-[3-(trifluoromethoxy)phenoxy]-1-buten-1-yl}octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoicacid

TLC: Rf 0.36 (ethyl acetate:methanol=9:1);

¹H-NMR (300 MHz, DMSO-d₆): δ 11.96, 7.39, 6.99-6.88, 5.55, 5.48, 5.11,4.60, 4.28, 3.90-3.83, 3.50, 2.83, 2.27, 2.15, 1.90-1.73, 1.67-1.20,1.12-0.85.

Example 17 (45): 4-[(3S, 5aR, 6R, 7R, 8aS)-6-{(1E,3R)-4-[2-fluoro-3-(trifluoromethyl)phenoxy]-3-hydroxy-1-buten-1-yl}-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl]butanoicacid

TLC: Rf 0.32 (ethyl acetate:methanol=9:1);

¹H-NMR (300 MHz, DMSO-d₆): δ 11.96, 7.53, 7.33-7.23, 5.55, 5.47, 5.18,4.61, 4.31, 4.03-3.95, 3.89-3.81, 3.50, 2.83, 2.27, 2.15, 1.90-1.69,1.65-1.17, 1.11-0.82.

Example 18 (1): 2-Propanyl 4-{(3S, 5aR, 6R, 7R,8aS)-7-hydroxy-6-[(3R)-3-hydroxy-4-phenoxybutyl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

Under the hydrogen atmosphere, palladium-carbon (15 mg) was added to a2-propanol solution (62 mL) of the compound (71 mg, 1.59 mmol) obtainedin Example 16 (1), and the mixture was stirred at room temperature for 3hours and 20 minutes. The reaction solution was filtered with Celite(trade name), concentrated under reduced pressure, and purified with acolumn apparatus (Hiflash-SI, Size S, ethyl acetate:hexane=1:1→ethylacetate) manufactured by Yamazen Corporation to obtain a titled compound(63 mg) having the following physical property values.

TLC: Rf 0.55 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.92-1.19, 1.22, 1.35-1.99, 2.15-2.29,2.33-2.59, 2.81-3.01, 3.58-4.18, 4.81-5.16, 6.78-7.11, 7.15-7.46.

Example 18 (2) to Example 18 (4)

Using the compounds produced in Example 16 (2), Example 16 (3) orExample 16 (25), and using dimethyl-(3-phenoxy-2-oxopropyl)-phosphonateor a corresponding phosphonic acid salt in place of it, these substanceswere subjected to the same objective operations as those of Example 18(1) to obtain the following Example compounds.

Example 18 (2): 2-Propanyl 4-{(3S, 5aR, 6R, 7R,8aS)-7-hydroxy-6-[(3R)-3-hydroxy-5-phenylpentyl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.82 (ethyl acetate:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.94-1.18, 1.22, 1.31-1.97, 2.12-2.30,2.59-2.73, 2.73-2.85, 2.85-2.95, 3.53-3.76, 3.86-4.08, 4.85-5.08,7.05-7.37.

Example 18 (3): 2-Propanyl 4-{(3S, 5aR, 6R, 7R,8aS)-6-[4-(3-chlorophenoxy)-3-hydroxybutyl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.58 (dichloromethane:methanol=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.70-1.99, 2.16-2.29, 2.30-2.64, 2.92,3.66-3.78, 3.78-3.87, 3.90-4.10, 4.89-5.09, 6.80, 6.91, 6.95, 7.20.

Example 18 (4): 2-Propanyl 4-{(3S, 5aR, 6R, 7R,8aS)-6-[4-(2,5-difluorophenoxy)-3-hydroxybutyl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

TLC: Rf 0.42 (isopropyl alcohol:hexane=1:5);

¹H-NMR (300 MHz, CDCl₃): δ 0.94-1.19, 1.19-1.25, 1.33-1.97, 2.13-2.73,2.91, 3.66-3.80, 3.81-4.16, 4.90-5.10, 6.52-6.65, 6.65-6.76, 6.93-7.09.

Example 19 (1) to Example 19 (4)

Using the compounds produced in Example 18 (1) to Example 18 (4), thesecompounds were subjected to the same objective operations as those ofExample 17 (1) to obtain the following Example compounds.

Example 19 (1): 4-{(3S, 5aR, 6R, 7R,8aS)-7-hydroxy-6-[(3R)-3-hydroxy-4-phenoxybutyl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.39 (dichloromethane:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.92-1.23, 1.36-1.98, 2.15-2.29, 2.33,2.84-2.99, 3.67-3.78, 3.79-3.87, 3.88-4.07, 6.81-7.04, 7.15-7.41.

Example 19 (2): 4-{(3S, 5aR, 6R, 7R,8aS)-7-hydroxy-6-[(3R)-3-hydroxy-5-phenylpentyl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.65 (ethyl acetate:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.94-1.18, 1.22, 1.31-1.97, 2.12-2.30,2.59-2.73, 2.73-2.85, 2.85-2.95, 3.53-3.76, 3.86-4.08, 4.85-5.08,7.05-7.37.

Example 19 (3): 4-{(3S, 5aR, 6R, 7R,8aS)-6-[4-(3-chlorophenoxy)-3-hydroxybutyl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.58 (dichloromethane:methanol=5:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.80-1.85, 1.85-2.06, 2.17-2.43, 2.91-3.04,3.53-3.68, 3.82-4.04, 6.83-6.89, 6.89-6.94, 6.95, 7.22.

Example 19 (4): 4-{(3S, 5aR, 6R, 7R,8aS)-6-[4-(2,5-difluorophenoxy)-3-hydroxybutyl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.41 (dichloromethane:methanol=10:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.93-1.24, 1.37-1.84, 1.84-2.01, 2.16-2.38,2.90-3.04, 3.50-3.70, 3.83-4.08, 6.53-6.71, 6.82-7.00, 6.99-7.15.

Example 20: Ethyl 2-({[(1R, 2S, 3R,4S)-2-allyl-3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]oxy}methyl)acrylate

Under the argon atmosphere, an anhydrous DMF (17 mL) solution of thecompound (3.9 g) produced in Example 3 was added to an anhydrous DMF (20mL) solution of sodium hydride (631 mg) under ice-cooling, and themixture was stirred at room temperature for 1 hour. Subsequently, ethyl2-(bromomethyl)acrylate (2.91 mL) was added, and the mixture was stirredat room temperature for 3 hours. An aqueous saturated ammonium chloridesolution was added, and this was extracted with hexane: ethyl acetate(2:1). After the organic layer was washed with water and a saturatedsaline, and dried with sodium sulfate, the solvent was concentratedunder reduced pressure. The resulting residue was purified with a columnapparatus (Hiflash-SI, Size 3 L, hexane:ethyl acetate=100:0→93:7→86:14)manufactured Yamazen Corporation to obtain a titled compound (4.32 g)having the following physical property values.

TLC: Rf 0.53 (hexane: ethyl acetate=5:1).

Example 21: Ethyl (5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-carboxylate

Under the argon atmosphere, the compound (200 mg, 0.190 mmol) producedin Example 20 was dissolved in toluene (40 mL). A Schrock's catalyst (48mg, 0.062 mmol) was added to react the compound at 60° C. for 18 hours.After allowing to stand, the reaction was concentrated, and purified bysilica gel column chromatography (hexane:ethyl acetate=95:10-50:50) toobtain a titled compound (3.2 mg) having the following physical propertyvalues. TLC: Rf 0.53 (hexane:ethyl acetate=4:1).

Example 22 (1): Ethyl (3S, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-carboxylateExample 22 (2): Ethyl (3R, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-carboxylate

Under the argon atmosphere, a 5% rhodium-alumina powder (160 mg) and,subsequently, ethanol (40 mL) were added to the compound (1.6 g)produced in Example 21, and the mixture was stirred at room temperaturefor 4 hours under the hydrogen atmosphere. The reaction solution wasfiltered with Celite (trade name), and concentrated under reducedpressure, and the resulting residue was purified with a column apparatus(Hiflash-SI, Size 3 L, hexane:ethyl acetate=95:5-8:2) manufactured byYamazen Corporation to obtain a compound (270 mg) of Example 22 (1) andits diastereomer (Example 22 (2) (1.2 g) having the following physicalproperty values.

The diastereomer (1.2 g) was dissolved in absolute ethanol (13 mL), a20% ethanol solution of sodium ethoxide (895 mg) was added at roomtemperature under the argon atmosphere, and the mixture was stirred atroom temperature overnight. After diluted with ethyl acetate, an aqueoussaturated ammonium chloride solution was added, and this was extractedwith ethyl acetate. After the organic layer was washed with water and asaturated saline, and dried with sodium sulfate, the solvent wasconcentrated under reduced pressure. The resulting residue was purifiedwith a column apparatus (Hiflash-SI, Size 3 L, hexane: ethylacetate=95:5→8:2) manufactured by Yamazen Corporation to obtain anExample compound 22 (1) (757 mg) having the following physical propertyvalues.

TLC: Rf 0.58 (hexane: ethyl acetate=4:1) (compound of Example 22 (1));

TLC: Rf 0.44 (hexane:ethyl acetate=5:1) (compound of Example 22 (2)).

Example 23: [(3R, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]methanol

Under the argon atmosphere, a THF (6.4 mL) solution of the compound (945mg) produced in Example 22 (1) was added to a THF (4 mL) solution oflithium aluminum hydride (87 mg) under ice-cooling, and the mixture wasstirred at room temperature for 20 minutes. After diluted with MTBE, anaqueous saturated sodium sulfate solution was added, filtered withCelite (trade name), and concentrated under reduced pressure to obtain atitled compound (884 mg) having the following physical property values.

TLC: Rf 0.16 (hexane:ethyl acetate=2:1).

Example 24: 2-methyl-2-propanyl {[(3R, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]methoxy}acetate

A 50% aqueous sodium hydroxide solution (0.6 mL) which had been preparedseparately was added to a benzene (1.8 mL) solution of the compound (300mg) produced in Example 23 under ice-cooling. Subsequently, atetrabutylammonium hydrogen sulfate salt (61 mg) and tert-butylbromoacetate (282 mg) were added, and the mixture was stirred at roomtemperature overnight. After diluted with MTBE, water was added, andthis was extracted with MTBE. The extract was washed with water and asaturated saline, and dried with sodium sulfate, and the solvent wasconcentrated under reduced pressure. The resulting residue was purifiedwith a column apparatus (SMB Silica Column, 10 μm, Size 60, hexane:ethylacetate=95:5→90:10→80:20→50:50) manufactured by Yamazen Corporation toobtain a titled compound (371 mg) having the following physical propertyvalues.

TLC: Rf 0.54 (hexane:ethyl acetate=4:1).

Example 25: {[(3R, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]methoxy}aceticacid

A 2N aqueous sodium hydroxide solution (1.75 mL) was added to a methanol(5.25 mL) solution of the compound (371 mg) produced in Example 24 atroom temperature, and the mixture was stirred at 50° C. for 3.5 hours.After methanol was distilled off by concentration under reducedpressure, the residue was diluted with MTBE, made acidic with ice-cooled2N hydrochloric acid, and extracted with ethyl acetate. The extract waswashed with water and a saturated saline, and dried with sodium sulfate,and the solvent was concentrated under reduced pressure to obtain atitled compound (371 mg) having the following physical property values.The resulting titled compound was used in a next reaction withoutpurification.

TLC: Rf 0.24 (ethyl acetate).

Example 26: 2-Propanyl {[(3R, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]methoxy}acetate

Under the argon atmosphere, the compound produced in Example 25 wasdissolved in DMF (2.8 mL), potassium carbonate (242 mg) and2-iodopropane (0.105 mL) were sequentially added at room temperature,and the mixture was stirred at 50° C. overnight. The reaction solutionwas diluted with ethyl acetate, water was added, and this was extractedwith ethyl acetate. The extract was washed with water and a saturatedsaline, and dried with sodium sulfate, and the solvent was concentratedunder reduced pressure to obtain a titled compound (371 mg) having thefollowing physical property values. The resulting titled compound wasused in a next reaction without purification.

TLC: Rf 0.81 (hexane: ethyl acetate=1:1).

Example 27: 2-Propanyl {[(3R, 5aR, 6S, 7R,8aS)-6-(hydroxymethyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]methoxy}acetate

Under the argon atmosphere, a 1M THF solution (1.4 mL) oftetrabutylammonium fluoride was added to the compound produced inExample 26 at room temperature, and the mixture was stirred for 6 hours.The reaction solution was diluted with ethyl acetate, an aqueoussaturated ammonium chloride solution was added, and this was extractedwith ethyl acetate. The extract was washed with water and a saturatedsaline, and dried with sodium sulfate, and the solvent was concentratedunder reduced pressure. The resulting residue was purified with a columnapparatus (Hiflash-SI, Size M, hexane:ethyl acetate=90:10→50:50→20:80)manufactured by Yamazen Corporation to obtain a titled compound (240 mg)having the following physical property values.

TLC: Rf 0.21 (hexane: ethyl acetate=1:1).

Example 28: 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

The compound (152 mg) produced in Example 27 was subjected to the sameobjective operations as those of Example 13→Example 14→Example15→Example 16 (1) using dimethyl-(3-phenoxy-2-oxopropyl)-phosphonate, toobtain a titled compound (72 mg) having the following physical propertyvalues.

TLC: Rf 0.33 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.10-1.31, 1.40-1.57, 1.58-2.19, 2.19-2.29,2.41-2.55, 2.61-2.73, 3.24-3.41, 3.63-3.81, 3.83-4.07, 4.14-4.25,4.42-4.60, 4.98-5.16, 5.58-5.73, 6.86-7.03, 7.23-7.34.

Example 28 (1) to Example 28 (17)

Using (3aR, 4S, 5R,6aS)-4-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one,using ethyl 2-(bromomethyl)acrylate, and usingdimethyl-(3-phenoxy-2-oxopropyl)-phosphonate or a correspondingphosphonic acid salt in place of it, these substances were subjected tothe same objective operations as those of Example 20→Example 21→Example22 (1) or Example 22 (2)→Example 23→Example 24→Example 25→Example26→Example 27→Example 28 to obtain the following Example compounds.

Example 28 (1): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.65 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.10-1.32, 1.40-1.60, 1.61-2.21, 2.40-2.56,3.05-3.18, 3.25-3.41, 3.67-3.82, 3.82-3.92, 3.92-4.06, 4.15-4.25,4.45-4.58, 4.99-5.17, 5.56-5.76, 6.75-6.84, 6.87-6.99, 7.15-7.24.

Example 28 (2): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.49 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.09-1.35, 1.39-2.24, 2.40-2.57, 2.62-2.78,3.10, 3.24-3.41, 3.64-3.80, 3.85-4.10, 4.14-4.26, 4.48-4.60, 4.98-5.15,5.55-5.77, 6.82-7.14.

Example 28 (3): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.45 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.07-1.34, 1.39-2.22, 2.37-2.58, 3.04-3.17,3.24-3.40, 3.64-3.80, 3.83-3.91, 3.91-4.07, 4.11-4.28, 4.45-4.59,4.95-5.17, 5.54-5.77, 6.53-6.74, 7.10-7.32.

Example 28 (4): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(4-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.42 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.10-1.34, 1.38-2.22, 2.39-2.57, 3.05-3.17,3.25-3.40, 3.65-3.79, 3.80-3.88, 3.88-4.09, 4.10-4.26, 4.43-4.58,4.97-5.15, 5.54-5.74, 6.77-6.91, 6.90-7.04.

Example 28 (5): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(4-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.57 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.10-1.30, 1.40-1.58, 1.61-2.22, 2.40-2.56,3.11, 3.25-3.41, 3.65-3.80, 3.80-3.90, 3.90-4.06, 4.13-4.25, 4.44-4.59,4.98-5.16, 5.55-5.75, 6.76-6.91, 7.16-7.30.

Example 28 (6): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(3-methylphenoxy)-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.60 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.09-1.31, 1.41-1.60, 1.61-2.22, 2.33,2.41-2.57, 3.05-3.17, 3.25-3.41, 3.66-3.81, 3.81-3.91, 3.92-4.06,4.14-4.26, 4.45-4.58, 4.99-5.16, 5.57-5.74, 6.66-6.83, 7.16.

Example 28 (7): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(4-methylphenoxy)-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.57 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.09-1.35, 1.40-1.59, 1.61-2.20, 2.29,2.39-2.60, 3.03-3.18, 3.25-3.41, 3.65-3.79, 3.79-3.89, 3.89-4.07,4.13-4.26, 4.44-4.56, 4.98-5.16, 5.56-5.74, 6.74-6.86, 7.07.

Example 28 (8): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.33 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.09-1.30, 1.40-1.57, 1.61-2.21, 2.40-2.56,2.71, 3.04-3.18, 3.25-3.41, 3.65-3.81, 3.88-4.04, 4.08, 4.15-4.24,4.52-4.62, 5.00-5.16, 5.95-5.76, 6.88-6.98, 7.17-7.28, 7.33-7.41.

Example 28 (9): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(2-methylphenoxy)-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.37 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.10-1.29, 1.41-1.57, 1.61-2.20, 2.24,2.41-2.55, 3.11, 3.25-3.40, 3.66-3.81, 3.86-3.94, 3.94-4.05, 4.20,4.48-4.60, 5.00-5.17, 5.60-5.76, 6.82, 6.85-6.93, 7.10-7.20.

Example 28 (10): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chloro-2-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.37 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.05-1.33, 1.38-2.25, 2.38-2.56, 2.65-2.74,2.96-3.19, 3.24-3.41, 3.73, 3.87-4.10, 4.14-4.26, 4.46-4.61, 4.98-5.15,5.56-5.75, 6.83-6.92, 6.93-7.05.

Example 28 (11): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3,5-dichlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.51 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.10-1.32, 1.38-2.24, 2.32-2.43, 2.43-2.57,3.05-3.19, 3.25-3.42, 3.65-3.82, 3.82-3.91, 3.92-4.06, 4.14-4.27,4.44-4.62, 4.99-5.18, 5.25-5.77, 6.82, 6.98.

Example 28 (12): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chloro-5-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.73 (ethyl acetate:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.10-1.37, 1.37-2.24, 2.39-2.59, 3.04-3.18,3.24-3.41, 3.65-3.80, 3.81-3.91, 3.91-4.05, 4.13-4.27, 4.43-4.58,4.99-5.16, 5.55-5.75, 6.48-6.59, 6.64-6.78.

Example 28 (13): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.79 (ethyl acetate:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.07-1.32, 1.37-2.22, 2.39-2.58, 3.04-3.18,3.24-3.41, 3.64-3.79, 3.81-3.90, 3.90-4.06, 4.12-4.27, 4.43-4.58,4.97-5.15, 5.55-5.74, 6.35-6.54.

Example 28 (14): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,3-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.77 (ethyl acetate:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.08-1.35, 1.36-2.32, 2.38-2.57, 2.63-2.84,3.03-3.19, 3.22-3.44, 3.62-3.82, 3.87-4.10, 4.13-4.28, 4.46-4.63,4.98-5.20, 5.54-5.77, 6.66-6.87, 6.90-7.05.

Example 28 (15): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.77 (ethyl acetate:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.07-1.32, 1.36-2.21, 2.27, 2.40-2.56, 2.77,3.04-3.20, 3.23-3.41, 3.64-3.80, 3.84-4.08, 4.13-4.27, 4.48-4.61,4.98-5.16, 5.54-5.74, 6.53-6.65, 6.65-6.76, 6.94-7.08.

Example 28 (16): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(5-chloro-2-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.52 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.10-1.30, 1.40-1.57, 1.61-2.21, 2.42-2.55,2.60, 3.05-3.17, 3.25-3.40, 3.66-3.82, 3.87-4.08, 4.15-4.25, 4.49-4.61,4.99-5.16, 5.55-5.75, 6.85-6.93, 6.93-7.06.

Example 28 (17): 2-Propanyl ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chloro-4-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)acetate

TLC: Rf 0.40 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.11-1.30, 1.40-1.60, 1.62-2.21, 2.41-2.55,3.05-3.17, 3.26-3.40, 3.66-3.79, 3.79-3.89, 3.89-4.06, 4.15-4.25,4.45-4.56, 4.99-5.15, 5.56-5.73, 6.73-6.80, 6.94, 7.00-7.09.

Example 29: ({(3R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

The compound (7.3 mg) produced in Example 28 was subjected to the sameobjective operations as those of Example 17 (1) to obtain a titledcompound (7.1 mg) having the following physical property values.

TLC: Rf 0.13 (chloroform:methanol:water=10:1:0.1)

¹H-NMR (300 MHz, CDCl₃): δ 1.08-1.23, 1.39-1.57, 1.59-1.95, 1.95-2.20,2.42-2.55, 3.03-3.16, 3.27-3.42, 3.66-3.78, 3.84-4.03, 4.05, 4.15-4.25,4.46-4.57, 5.56-5.74, 6.86-7.02, 7.23-7.33.

Example 29 (1) to Example 29 (17)

The compounds produced in Example 28 (1) to Example 28 (17) weresubjected to the same objective operations as those of Example 29,respectively, to obtain the following Example compounds.

Example 29 (1): ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.21 (chloroform:methanol:acetic acid=20:1:0.1);

¹H-NMR (300 MHz, CDCl₃): δ 1.09-1.31, 1.40-2.26, 2.42-2.57, 3.03-3.17,3.29-3.46, 3.68-3.81, 3.82-3.91, 3.93-4.09, 4.14-4.23, 4.46-4.58,5.57-5.75, 6.75-6.84, 6.87-6.99, 7.14-7.24.

Example 29 (2): ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.23 (chloroform:methanol=5:1);

¹H-NMR (300 MHz, CD₃OD): δ 1.07-1.24, 1.32-1.48, 1.49-1.63, 1.67-2.13,2.35-2.51, 3.06-3.18, 3.20-3.42, 3.59-3.74, 3.90-4.08, 4.11-4.23,4.38-4.49, 5.57-5.70, 6.83-6.95, 6.99-7.16.

Example 29 (3): ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.26 (chloroform:methanol=5:1);

¹H-NMR (300 MHz, CD₃OD): δ 1.09-1.24, 1.35-1.49, 1.49-1.61, 1.67-2.12,2.37-2.50, 3.07-3.18, 3.21-3.40, 3.60-3.72, 3.83-4.05, 4.13-4.23,4.34-4.47, 5.56-5.73, 6.56-6.83, 7.16-7.32.

Example 29 (4): ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(4-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.24 (chloroform:methanol=5:1);

¹H-NMR (300 MHz, CD₃OD): δ 1.09-1.24, 1.34-1.49, 1.49-1.61, 1.68-2.11,2.35-2.51, 3.08-3.19, 3.20-3.42, 3.60-3.73, 3.80-4.07, 4.12-4.24,4.34-4.46, 5.56-5.71, 6.83-7.06.

Example 29 (5): ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(4-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.42 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 1.06-1.28, 1.32-1.63, 1.64-2.12, 2.35-2.51,3.06-3.19, 3.20-3.43, 3.57-3.74, 3.81-4.10, 4.10-4.24, 4.33-4.47,5.52-5.73, 6.84-6.97, 7.16-7.29.

Example 29 (6): ({(3R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(3-methylphenoxy)-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.43 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 1.07-1.26, 1.33-1.64, 1.66-2.13, 2.29,2.37-2.51, 3.05-3.19, 3.20-3.44, 3.57-3.75, 3.82-4.08, 4.10-4.24,4.32-4.47, 5.54-5.72, 6.62-6.80, 7.04-7.17.

Example 29 (7): ({(3R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(4-methylphenoxy)-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.45 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 1.06-1.27, 1.31-1.64, 1.65-2.11, 2.25,2.35-2.52, 3.04-3.20, 3.19-3.43, 3.58-3.74, 3.77-4.10, 4.10-4.24,4.31-4.46, 5.52-5.72, 6.79, 7.04.

Example 29 (8): ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.18 (chloroform:methanol:water-10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 1.09-1.23, 1.32-1.46, 1.48-1.62, 1.68-2.11,2.36-2.51, 3.11, 3.22-3.40, 3.60-3.73, 3.86-4.06, 4.12-4.22, 4.40-4.50,5.58-5.73, 6.90, 7.05, 7.23, 7.33.

Example 29 (9): ({(3R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(2-methylphenoxy)-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.18 (chloroform:methanol:water=10:1:0.1)

¹H-NMR (300 MHz, CD₃OD): δ 1.08-1.22, 1.34-1.49, 1.55, 1.68-2.10, 2.20,2.43, 3.07-3.17, 3.25-3.39, 3.66, 3.86-4.07, 4.17, 4.38-4.47, 5.57-5.73,6.76-6.89, 7.04-7.14.

Example 29 (10): ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chloro-2-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.29 (dichloromethane:methanol=5:1);

¹H-NMR (300 MHz, CD₃OD): δ 1.05-1.62, 1.63-2.09, 2.35-2.52, 3.06-3.19,3.19-3.42, 3.58-3.73, 3.93-4.06, 4.12-4.22, 4.37-4.52, 5.52-5.74,6.89-7.18.

Example 29 (11): ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3,5-dichlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.24 (dichloromethane:methanol=5:1);

¹H-NMR (300 MHz, CD₃OD): δ 1.06-1.62, 1.65-2.13, 2.37-2.52, 3.07-3.18,3.20-3.45, 3.60-3.74, 3.82-4.07, 4.12-4.23, 4.33-4.47, 5.53-5.73, 6.93,6.98.

Example 29 (12): ({(3R, 5aR, 6R, 7R,8aS)-6-[(1E,3R)-4-(3-chloro-5-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.46 (dichloromethane:methanol:acetic acid=3:1:0.2);

¹H-NMR (300 MHz, CD₃OD): δ 1.07-1.33, 1.32-1.63, 1.63-2.13, 2.36-2.50,3.06-3.18, 3.20-3.41, 3.60-3.73, 3.84-4.07, 4.12-4.23, 4.35-4.46,5.53-5.72, 6.68, 6.75, 6.79-6.85.

Example 29 (13): ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.47 (dichloromethane:methanol:acetic acid=3:1:0.2);

¹H-NMR (300 MHz, CD₃OD): δ 1.08-1.30, 1.32-1.63, 1.68-2.12, 2.36-2.51,3.06-3.18, 3.21-3.41, 3.59-3.74, 3.82-4.06, 4.12-4.24, 4.35-4.48,5.54-5.73, 6.39-6.64.

Example 29 (14): ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,3-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.48 (dichloromethane:methanol:acetic acid=3:1:0.2);

¹H-NMR (300 MHz, CD₃OD): δ 1.08-1.28, 1.33-1.61, 1.65-2.12, 2.36-2.52,3.12, 3.20-3.42, 3.58-3.73, 3.90-4.07, 4.11-4.22, 4.38-4.49, 5.53-5.73,6.75-6.86, 6.86-6.95, 6.97-7.11.

Example 29 (15): ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.48 (dichloromethane:methanol:acetic acid=3:1:0.2);

¹H-NMR (300 MHz, CD₃OD): δ 1.06-1.24, 1.32-1.65, 1.66-2.13, 2.35-2.52,3.05-3.18, 3.22-3.42, 3.58-3.73, 3.88-4.07, 4.11-4.24, 4.37-4.51,5.53-5.74, 6.54-6.69, 6.84-6.96, 6.99-7.14.

Example 29 (16): ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(5-chloro-2-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.12 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 1.07-1.24, 1.33-1.49, 1.49-1.62, 1.67-2.10,2.36-2.51, 3.07-3.19, 3.19-3.42, 3.60-3.72, 3.93-4.07, 4.11-4.23,4.38-4.48, 5.55-5.72, 6.90, 7.07, 7.13.

Example 29 (17): ({(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chloro-4-fluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}methoxy)aceticacid

TLC: Rf 0.11 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 1.08-1.25, 1.34-1.63, 1.67-2.09, 2.37-2.51,3.07-3.18, 3.20-3.42, 3.59-3.73, 3.82-4.07, 4.12-4.23, 4.35-4.44,5.54-5.72, 6.87, 7.04, 7.12.

Example 30: 2-Propanyl 4-[(3S, 5aR, 6R, 7R,8aS)-6-[(1E)-3,3-difluoro-4-phenoxy-1-buten-1-yl]-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

Under the argon atmosphere, the compound (280 mg, 0.53 mmol) produced inExample 14 was dissolved in (2-methoxyethyl)aminosulfur trifluoride (977μL, 5.30 mmol), and the mixture was stirred at room temperature for 4days and 7 hours. The reaction solution was slowly poured into anice-cooled aqueous saturated sodium bicarbonate solution, and theaqueous layer was extracted with ethyl acetate two times. The organiclayer was washed with a saturated saline, and dried with anhydroussodium sulfate. Purification with a column apparatus (Hiflash-SI, SizeM, hexane-ethyl acetate:hexane=3:7) manufactured by Yamazen Corporationafforded a titled compound (171 mg) having the following physicalproperty values.

TLC: Rf 0.54 (hexane:ethyl acetate=3:7).

Example 31: 2-Propanyl 4-{(3S, 5aR, 6R, 7R,8aS)-6-[(1E)-3,3-difluoro-4-phenoxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

The compound produced in Example 30 was subjected to the same objectiveoperations as those of Example 16 (1) to obtain a titled compound havingthe following physical property values.

TLC: Rf 0.42 (ethyl acetate:hexane=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.87-1.19, 1.18-1.26, 1.35-1.96, 2.11-2.30,2.35-2.56, 2.84-2.97, 3.67-3.84, 3.90-4.11, 4.19, 4.89-5.08, 5.68-5.87,5.95-6.11, 6.85-6.95, 6.95-7.05, 7.21-7.35.

Example 32: 4-{(3 S, 5aR, 6R, 7R,8aS)-6-[(1E)-3,3-difluoro-4-phenoxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

The compound produced in Example 31 was subjected to the same objectiveoperations as those of Example 17 (1) to obtain a titled compound havingthe following physical property values.

TLC: Rf 0.34 (dichloromethane:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.90-1.23, 1.36-1.96, 2.12-2.27, 2.33,2.40-2.53, 2.84-2.98, 3.71-3.83, 3.90-4.10, 4.19, 5.69-5.88, 5.95-6.10,6.86-6.94, 6.95-7.05, 7.21-7.35.

Example 32 (1) to Example 32 (5)

Using the compound produced in Example 13, and using a correspondingphosphonic acid salt in place ofdimethyl-(3-phenoxy-2-oxopropyl)-phosphonate, these substances weresubjected to the same objective operations as those of Example14→Example 30→Example 31→Example 32 to obtain the following Examplecompounds.

Example 32 (1): 4-{(3S, 5aR, 6R, 7R,8aS)-6-[(1E)-3,3-difluoro-4-(2-fluorophenoxy)-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.52 (ethyl acetate);

¹H-NMR (300 MHz, DMSO-d₆): δ 11.98, 7.28-7.19, 7.13, 6.99, 6.06, 5.75,4.79, 4.43, 3.90-3.84, 3.57, 2.84, 2.30, 2.15, 1.97, 1.80-1.64,1.61-1.21, 1.11-0.86.

Example 32 (2): 4-{(3S, 5aR, 6R, 7R,8aS)-6-[(1E)-3,3-difluoro-4-(3-fluorophenoxy)-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.55 (ethyl acetate);

¹H-NMR (300 MHz, DMSO-d₆): δ 11.98, 7.33, 6.94-6.78, 6.05, 5.75, 4.81,4.39, 3.91-3.85, 3.58, 2.85, 2.31, 2.16, 1.98, 1.81-1.67, 1.60-1.22,1.12-0.87.

Example 32 (3): 4-{(3S, 5aR, 6R, 7R,8aS)-6-[(1E)-4-(3-chlorophenoxy)-3,3-difluoro-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.55 (ethyl acetate);

¹H-NMR (300 MHz, DMSO-d₆): δ 11.98, 7.32, 7.11, 7.04, 6.98, 6.05, 5.74,4.80, 4.40, 3.91-3.84, 3.58, 2.84, 2.31, 2.16, 1.97, 1.81-1.64,1.59-1.21, 1.10-0.86.

Example 32 (4): 4-[(3S, 5aR, 6R, 7R,8aS)-6-{(1E)-3,3-difluoro-4-[3-(trifluoromethyl)phenoxy]-buten-1-yl}-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl]butanoicacid

TLC: Rf 0.68 (ethyl acetate);

¹H-NMR (300 MHz, DMSO-d₆): δ 11.98, 7.55, 7.35-7.32, 6.06, 5.76, 4.80,4.48, 3.91-3.84, 3.58, 2.84, 2.31, 2.16, 1.98, 1.81-1.64, 1.59-1.21,1.10-0.86.

Example 32 (5): 4-{(3 S, 5aR, 6R, 7R,8aS)-6-[(1E)-4-(2,5-difluorophenoxy)-3,3-difluoro-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.65 (ethyl acetate);

¹H-NMR (300 MHz, DMSO-d₆): δ 11.98, 7.33-7.23, 6.82, 6.07, 5.74, 4.80,4.48, 3.91-3.84, 3.58, 2.85, 2.31, 2.16, 1.97, 1.81-1.64, 1.60-1.21,1.10-0.86.

Example 33: [(3S, 5aR, 6S, 7R,8aS)-6-(hydroxymethyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]methylacetate

Pyridine (0.335 mL), acetic acid anhydride (0.294 mL) andN-dimethylaminopyridine (small amount) were sequentially added to adichloromethane (5 mL) solution of the compound (884 mg) produced inExample 23 at room temperature, and the mixture was stirred for 3 hours.This was diluted with ethyl acetate, and water was added, followed byextraction with ethyl acetate. The organic layer was sequentially washedwith 1N hydrochloric acid, an aqueous saturated sodium bicarbonatesolution, and a saturated saline, and dried with sodium sulfate, and thesolvent was concentrated under reduced pressure. To the resultingresidue was added THF (0.5 mL), a 1M THF solution (5 mL) ofN-tetrabutylammonium fluoride was added under the argon atmosphere andice-cooling, and the mixture was stirred for 5 hours. The reactionsolution was poured into an ice-cooled aqueous saturated ammoniumchloride solution, and this was extracted with ethyl acetate. Theorganic layer was washed with water, and a saturated saline, and driedwith sodium sulfate, and the solvent was concentrated under reducedpressure. The resulting residue was purified by preparativechromatograph (Hiflash-SI, Size L, hexane:ethyl acetate=8:2→1:1→0:1)manufactured Yamazen Corporation to obtain a titled compound (616 mg)having the following physical property values.

TLC: Rf 0.19 (hexane:ethyl acetate=1:1).

Example 34: [(3S, 5aR, 6R, 7R,8aS)-6-[(1E)-3-oxo-4-phenoxy-1-buten-1-yl]-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]methylacetate

The compound (616 mg) produced in Example 33 was subjected to the sameobjective operations as those of Example 13→Example 14 to obtain atitled compound (568 mg) having the following physical property values.

TLC: Rf 0.53 (hexane: ethyl acetate=1:1).

Example 35: [(3R, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-phenoxy-3-(tetrahydro-2H-pyran-2-yloxy)-1-buten-1-yl]-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]methanol

The compound produced in Example 34 was subjected to the same objectiveoperations as those of Example 15→Example 11 to obtain a titled compound(568 mg) having the following physical property values.

TLC: Rf 0.26 (hexane:ethyl acetate=1:1).

Example 36: Ethyl 2-[(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3S)-4-phenoxy-3-(tetrahydro-2H-pyran-2-yloxy)-1-buten-1-yl]-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]-1,3-thiazole-4-carboxylate

Under the argon atmosphere, diisopropylethylamine (0.3 mL) was added toa DMSO (0.5 mL)-ethyl acetate (1.0 mL) solution of the compound (150 mg)synthesized in Example 35 under ice-cooling, subsequently,pyridine-sulfur trioxide (139 mg) were added, and the mixture wasstirred for about 30 minutes. After dilution with ethyl acetate, anaqueous saturated ammonium chloride solution was added, and this wasextracted with ethyl acetate. The organic layer was washed with anaqueous saturated ammonium chloride solution, an aqueous saturatedsodium bicarbonate solution, water and a saturated saline, dried withsodium sulfate, and concentrated under reduced pressure. The resultingresidue was dissolved in toluene (1.5 mL), triethylamine (0.061 mL) andL-cysteine ethyl ester hydrochloride (81 mg) were sequentially addedunder ice-cooling, and the mixture was stirred at room temperatureovernight. After dilution with ethyl acetate, water was added, and thiswas extracted with ethyl acetate. The extract was sequentially washedwith an aqueous citric acid solution, an aqueous saturated sodiumbicarbonate solution, water and a saturated saline, dried with sodiumsulfate, and concentrated under reduced pressure. The resulting residuewas dissolved in toluene (5.8 mL), manganese dioxide (756 mg) was added,and the mixture was stirred at 60° C. overnight. This was filtered withCelite (trade name), and washed with ethyl acetate plural times, and thefiltrate was concentrated under reduced pressure. The resulting residuewas purified with preparative chromatograph (SMB Silica Column 10 μm,Size 20, hexane:ethyl acetate=9:1→75:25→6:4→3:7) manufactured by YamazenCorporation to obtain a title compound (65 mg) having the followingphysical property values.

TLC: Rf 0.42, 0.38 (hexane:ethyl acetate=3:2).

Example 37: Ethyl 2-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}-1,3-thiazole-4-carboxylate

To an ethanol (1.0 mL) solution of the compound (65 mg) produced inExample 36 was added p-toluenesulfonic acid monohydrate (2.0 mg) at roomtemperature, and the mixture was stirred overnight. An aqueous saturatedsodium bicarbonate solution was added, and this was extracted with ethylacetate. The extract was washed with water and a saturated saline, driedwith sodium sulfate, and concentrated under reduced pressure. Theresulting residue was purified with preparative chromatograph (SMBsilica column, 10 μm, Size 20, hexane:ethyl acetate=1:1-0:1)manufactured by Yamazen Corporation to obtain a titled compound (47 mg)having the following physical property values.

TLC: Rf 0.65 (ethyl acetate:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.39, 1.59-1.97, 2.04, 2.10-2.35, 2.45-2.60,3.39-3.56, 3.69-3.83, 3.89, 3.97-4.05, 4.10, 4.31-4.47, 4.49-4.60,5.61-5.76, 6.86-7.01, 7.24-7.34, 8.04.

Example 38: 2-{(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}-1,3-thiazole-4-carboxylicacid

The compound produced in Example 37 was subjected to the same objectiveoperations as those of Example 17 (1) to obtain a titled compound havingthe following physical property values.

TLC: Rf 0.19 (chloroform:methanol:water=10:1:0.1);

¹H-NMR (300 MHz, CDCl₃): δ 1.56-2.01, 2.10-2.39, 2.47-2.61, 3.35-3.55,3.78, 3.85-3.94, 3.97-4.06, 4.11, 4.38, 4.51-4.60, 5.63-5.77, 6.87-7.02,7.23-7.35, 8.15.

Example 39: Ethyl ({[(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-phenoxy-3-(tetrahydro-2H-pyran-2-yloxy)-1-buten-1-yl]-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]methyl}thio)acetate

Triethylamine (0.039 mL) and methanesulfonic acid chloride (0.020 mL)were sequentially added to an anhydrous THF (1.7 mL) solution of thecompound (90 mg) produced in Example 35 under ice-cooling, and themixture was stirred for 1 hour. This was diluted with ethyl acetate, andwater was added, followed by extraction. The extract was sequentiallywashed with an aqueous saturated sodium bicarbonate solution, water anda saturated saline, and dried with sodium sulfate. The solvent wasconcentrated under reduced pressure to obtain the residue (109 mg). Theresulting residue was dissolved in an anhydrous THF (1.7 mL) solution,and ethyl thioglycolate (0.029 mL) was added. Subsequently, 60% sodiumhydride (11 mg) was added at room temperature, and the mixture wasstirred at 50° C. overnight. This was diluted with ethyl acetate, andwater was added, followed by extraction. The extract was sequentiallywashed with an aqueous saturated sodium bicarbonate solution, water anda saturated saline, and dried with sodium sulfate. The solvent wasconcentrated under reduced pressure, and the resulting residue waspurified by preparative chromatograph (Hiflash-SI, Size S, hexane:ethylacetate=75:25→0:100) manufactured by Yamazen Corporation to obtain atitled compound (61 mg) having the following physical property values.

TLC: Rf 0.81 (hexane: ethyl acetate=1:2).

Example 40: Ethyl [({(3 S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}methyl)thio]acetate

The compound produced in Example 39 was subjected to the same objectiveoperations as those of Example 37 to obtain a titled compound having thefollowing physical property values.

TLC: Rf 0.16 (hexane: ethyl acetate=1:2);

¹H-NMR (300 MHz, CDCl₃): δ 1.00-1.18, 1.24-1.33, 1.38-1.56, 1.56-1.85,1.84-2.19, 2.25, 2.39-2.55, 2.68, 2.98, 3.13-3.22, 3.64-3.79, 3.83-3.92,3.92-4.03, 4.09-4.26, 4.45-4.58, 5.57-5.72, 6.85-7.02, 7.22-7.34.

Example 41: [({(3S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}methyl)thio]aceticacid

The compound produced in Example 40 was subjected to the same objectiveoperations as those of Example 17 (1) to obtain a titled compound havingthe following physical property values.

TLC: Rf 0.35 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CDCl₃): δ 1.01-1.17, 1.38-1.55, 1.60-1.86, 1.86-2.20,2.41-2.55, 2.93-3.05, 3.22, 3.67-3.79, 3.84-3.93, 3.93-4.04, 4.14-4.24,4.48-4.57, 5.59-5.74, 6.87-7.03, 7.24-7.34.

Example 42 (1) to Example 42 (2)

Using the compound produced in Example 4, and using a correspondingorganozinc reagent in place of 4-ethyoxy-4-oxobutylzinc bromide, thesesubstances were subjected to the same objective operations as those ofExample 5→Example 6→Example 12→Example 13→Example 14→Example 15→Example16 (1) to obtain the following compounds.

Example 42 (1): Ethyl 3-{(5aR, 6R, 7R,8aS)-7-hydroxy-6-[(1E)-3-hydroxy-4-phenoxy-1-buten-1-yl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}benzoate(low polar body)

TLC: Rf 0.43 (hexane:ethyl acetate=1:2);

¹H-NMR (300 MHz, CDCl₃): δ 1.35-1.44, 1.71-1.86, 2.04, 2.11-2.32,2.43-2.64, 2.64-2.86, 3.73-3.94, 4.02, 4.07-4.21, 4.31-4.50, 4.50-4.61,4.81-4.95, 5.61-5.81, 5.96-6.10, 6.86-7.03, 7.21-7.46, 7.84-7.98.

Example 42 (2): Ethyl 3-{(5aR, 6R, 7R,8aS)-7-hydroxy-6-[(1E)-3-hydroxy-4-phenoxy-1-buten-1-yl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}benzoate(high polar body)

TLC: Rf 0.33 (hexane:ethyl acetate=1:2);

¹H-NMR (300 MHz, CDCl₃): δ 1.40, 1.72-1.86, 2.08-2.32, 2.44-2.58, 2.61,2.75, 3.74-3.86, 3.85-3.96, 3.98-4.07, 4.15, 4.33-4.51, 4.55, 4.83-4.95,5.62-5.80, 5.97-6.08, 6.88-7.03, 7.23-7.46, 7.88-7.96.

Example 43 (1) to Example 43 (5)

Using the compound produced in Example 4, using 4-ethoxy-4-oxobutylzincbromide or a corresponding organozinc reagent in place of it, and usingdimethyl-(3-phenoxy-2-oxopropyl)-phosphonate or a correspondingphosphonic acid salt in place of it, these substances were subjected tothe same objective preparations as those of Example 5→Example 6→Example12→Example 13→Example 14→Example 15→Example 16 (1)→Example 17 (1) toobtain the following Example compounds.

Example 43 (1): 3-{(5aR, 6R, 7R,8aS)-7-hydroxy-6-[(1E)-3-hydroxy-4-phenoxy-1-buten-1-yl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}benzoicacid (low polar body)

TLC: Rf 0.19 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 1.58-1.74, 2.07-2.32, 2.40-2.55, 2.60-2.78,3.66-3.80, 3.84-3.95, 3.95-4.04, 4.10-4.22, 4.38-4.56, 4.77-4.99,5.62-5.79, 6.04, 6.85-6.99, 7.19-7.29, 7.39, 7.45-7.54, 7.83-7.94.

Example 43 (2): 3-{(5aR, 6R, 7R,8aS)-7-hydroxy-6-[(1E)-3-hydroxy-4-phenoxy-1-buten-1-yl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}benzoicacid (high polar body)

TLC: Rf 0.20 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 1.58-1.74, 2.04-2.31, 2.40-2.55, 2.66,3.66-3.81, 3.86-4.02, 4.15, 4.37-4.54, 4.73-5.00, 5.59-5.76, 6.01,6.85-6.98, 7.19-7.30, 7.39, 7.45-7.53, 7.84-7.94.

Example 43 (3): 3-{(5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}propanoicacid

TLC: Rf 0.56 (dichloromethane:methanol=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.61-1.79, 1.84-2.29, 2.36-2.60, 3.67-3.83,3.86-4.16, 4.38, 4.48-4.67, 5.41-5.57, 5.57-5.87, 6.78-7.08, 7.19-7.36.

Example 43 (4): 4-{(5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.38 (dichloromethane:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.62-1.79, 1.81-2.26, 2.26-2.64, 3.69-3.81,3.82-3.91, 3.92-4.07, 4.39, 4.49-4.59, 5.42-5.53, 5.55-5.79, 6.75-7.12,7.19-7.41.

Example 43 (5): 4-{(5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3S)-3-hydroxy-1-octen-1-yl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.33 (dichloromethane:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.68-1.01, 1.06-2.93, 3.58-3.87, 3.88-4.24,4.38, 5.25-5.81.

Example 44 (1) to Example 44 (4)

Using the compound produced in Example 4, and using4-ethoxy-4-oxobutylzinc bromide or a corresponding organozinc reagent inplace of it, these substances were subjected to the same objectiveoperations as those of Example 5→Example 6→Example 7→Example 8→Example12→Example 13→Example 14→Example 15→Example 16 (1) to obtain thefollowing Example compounds.

Example 44 (1): 2-propanyl 5-{(5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}pentanoate

TLC: Rf 0.21 (hexane:ethyl acetate=1:2);

¹H-NMR (300 MHz, CDCl₃): δ 1.22, 1.31-1.44, 1.51-1.78, 1.77-1.98,2.01-2.31, 2.37-2.61, 3.49, 3.68-3.82, 3.83-3.93, 3.93-4.06, 4.39,4.47-4.59, 4.92-5.06, 5.37-5.49, 5.57-5.75, 6.86-7.02, 7.22-7.35.

Example 44 (2): 2-propanyl 5-{(5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxy-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}pentanoate

TLC: Rf 0.26 (hexane:ethyl acetate=2:3);

¹H-NMR (300 MHz, CDCl₃): δ 1.22, 1.31-1.46, 1.52-1.65, 1.65-1.77,1.77-1.97, 2.01-2.32, 2.37-2.65, 3.68-3.82, 3.82-3.92, 3.92-4.05, 4.39,4.51, 4.91-5.08, 5.39-5.50, 5.57-5.75, 6.77-6.84, 6.89-6.99, 7.20.

Example 44 (3): 2-propanyl 5-{(5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(3-methylphenoxy)-1-buten-1-yl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}pentanoate

TLC: Rf 0.29 (hexane:ethyl acetate=1:2);

¹H-NMR (300 MHz, CDCl₃): δ 1.20-1.25, 1.31-1.45, 1.51-1.65, 1.65-1.77,1.77-1.98, 2.00-2.21, 2.21-2.30, 2.30-2.36, 2.38-2.61, 3.68-3.80,3.81-3.91, 3.91-4.06, 4.32-4.45, 4.51, 4.92-5.07, 5.38-5.49, 5.57-5.74,6.66-6.83, 7.16.

Example 44 (4): 2-propanyl 6-{(5aR, 6R, 7R,8aS)-7-hydroxy-6-[(1E)-3-hydroxy-4-phenoxy-1-buten-1-yl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}hexanoate

TLC: Rf 0.15 (hexane:ethyl acetate=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.18-1.46, 1.52-1.99, 2.00-2.30, 2.30-2.62,2.77, 3.65-3.81, 3.81-4.08, 4.39, 4.46-4.59, 4.90-5.09, 5.42, 5.55-5.75,6.85-7.03, 7.22-7.35.

Example 45 (1) to Example 45 (4)

The compounds produced in Example 44 (1) to Example 44 (4) weresubjected to the same objective operations as those of Example 17 (1) toobtain the following Example compounds.

Example 45 (1): 5-{(5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}pentanoicacid

TLC: Rf 0.53 (ethyl acetate:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.31-1.48, 1.52-1.77, 1.77-1.98, 2.00-2.25,2.34, 2.38-2.59, 3.67-3.81, 3.84-4.06, 4.38, 4.46-4.58, 5.43, 5.57-5.73,6.85-7.02, 7.21-7.35.

Example 45 (2): 5-{(5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxy-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}pentanoicacid

TLC: Rf 0.36 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CDCl₃): δ 1.22-1.49, 1.53-1.76, 1.78-1.98, 1.98-2.28,2.34, 2.38-2.57, 3.67-3.80, 3.84-3.93, 3.93-4.05, 4.32-4.44, 4.45-4.55,5.44, 5.56-5.73, 6.77-6.84, 6.89-6.98, 7.20.

Example 45 (3): 5-{(5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-(3-methylphenoxy)-1-buten-1-yl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}pentanoicacid

TLC: Rf 0.43 (chloroform:methanol:acetic acid=10:1:0.1):

¹H-NMR (300 MHz, CD₃OD): δ 1.32-1.47, 1.49-1.65, 1.79-1.94, 2.01-2.13,2.21-2.34, 2.34-2.54, 3.62-3.75, 3.83-4.08, 4.32-4.45, 5.44, 5.54-5.72,6.66-6.78, 7.06-7.17.

Example 45 (4): 6-{(5aR, 6R, 7R,8aS)-7-hydroxy-6-[(1E)-3-hydroxy-4-phenoxy-1-buten-1-yl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}hexanoicacid

TLC: Rf 0.57 (chloroform:methanol:acetic acid=10:1:0.1);

¹H-NMR (300 MHz, CD₃OD): δ 1.22-1.46, 1.50-1.67, 1.77-1.94, 1.98-2.13,2.27, 2.36-2.55, 3.60-3.76, 3.85-4.08, 4.31-4.47, 5.38-5.48, 5.56-5.72,6.86-6.97, 7.20-7.30.

Example 46: Ethyl 4-{(5aR, 6R, 7R,8aS)-7-hydroxy-6-[(1E)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate(diastereomer mixture)

Using the compound produced in Example 6, this compound was subjected tothe same objective preparations as those of Example 9→Example 12→Example13→Example 14→Example 15♯Example 16 (1) to obtain a titled compoundhaving the following physical property values.

TLC: Rf 0.33 (dichloromethane:methanol=20:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.21-1.34, 1.37-1.89, 2.09-2.53, 2.57-2.67,3.41, 3.66-4.06, 4.07-4.23, 4.45-4.56, 5.57-5.73, 6.87-7.05, 7.20-7.36.

Example 47: 4-{(5aR, 6R, 7R,8aS)-7-hydroxy-6-[(1E)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid (diastereomer mixture)

Using the compound produced in Example 46, this compound was subjectedto the same objective operations as those of Example 17 (1) to obtain atitled compound having the following physical property values.

TLC: Rf 0.36 (dichloromethane:methanol=10:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.09-1.88, 2.08-2.23, 2.26-2.59, 2.85-3.55,3.60-4.17, 4.45-4.60, 5.52-5.84, 6.84-7.03, 7.13-7.43.

Example 48 (1) to Example 48 (2)

Using the compound produced in Example 3, and using a correspondingalkyl halide in place of 2,3-dibromopropene, these substances weresubjected to the same objective preparations as those of Example4→Example 5→Example 6→Example 7→Example 8→Example 9→Example 12→Example13→Example 14→Example 15→Example 16 (1) to obtain the following Examplecompounds.

Example 48 (1): 2-propanyl 3-{(5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}propanoate(diastereomer mixture)

TLC: Rf 0.47 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.23, 1.33-1.94, 2.01-2.60, 2.86-3.46,3.66-4.09, 4.47-4.59, 4.92-5.07, 5.58-5.75, 6.86-7.02, 7.24-7.35.

Example 48 (2): 2-propanyl 5-{(5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}pentanoate(diastereomer mixture)

TLC: Rf 0.19 (hexane:ethyl acetate=1:2);

¹H-NMR (300 MHz, CDCl₃): δ 0.87-2.03, 2.03-2.33, 2.33-2.57, 2.89,3.65-4.10, 4.46-4.59, 4.91-5.07, 5.57-5.74, 6.86-7.02, 7.19-7.34.

Example 49 (1) to Example 49 (2)

The compounds produced in Example 48 (1) to Example 48 (2) weresubjected to the same objective operations as those of Example 17 (1) toobtain the following Example compounds.

Example 49 (1): 3-{(5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}propanoicacid (diastereomer mixture)

TLC: Rf 0.51 (chloroform:methanol:water=10:1:0.1);

¹H-NMR (300 MHz, CDCl₃): δ 1.30-1.96, 2.06-2.55, 2.85-3.47, 3.57-4.10,4.41-4.61, 5.55-5.74, 6.86-7.02, 7.22-7.37.

Example 49 (2): 5-{(5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}pentanoicacid (diastereomer mixture)

TLC: Rf 0.53 (ethyl acetate:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.88-1.19, 1.20-1.52, 1.52-1.93, 2.05-2.19,2.27-2.39, 2.40-2.54, 2.89, 3.64-3.77, 3.77-4.08, 4.44-4.57, 5.55-5.72,6.85-7.03, 7.21-7.36.

Example 50: (1S, 2R, 3 S,4R)-3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-2-(1-propen-1-yl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol

Under the argon atmosphere,carbonylchlorohydridotris(triphenylphosphine)ruthenium (9.5 mg) wasadded to a toluene solution (1 mL) of the compound (74.1 mg) produced inExample 3, and the reaction mixture was stirred at 80° C. for 3 hoursand 30 minutes. Thereafter, a small amount of the reaction mixture wastaken, and concentrated to obtain a titled compound having the followingphysical property values.

TLC: Rf 0.45 (hexane:ethyl acetate=75:25).

Example 51: 2-methyl-2-propanyl {[(1S, 2R, 3S,4R)-3-({([dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-2-(1-propen-1-yl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]oxy}acetate

Under the argon atmosphere, the compound (3.70 g) produced in Example 50was dissolved in DMF (20 mL). After t-butyl bromoacetate (7.4 mL) wasadded, sodium hydride (400 mg, 60% in oil) was added four times forevery 30 minutes to 60 minutes (total 1600 mg). After stirring at roomtemperature overnight, water was added to the reaction mixture, theextract obtained by extraction with ethyl acetate was washed with waterand a saturated salineoo, dried with anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane: ethyl acetate=95:5→75:25) to obtain atitled compound (3.5 g) having the following physical property values.

TLC: Rf 0.50 (hexane:ethyl acetate=80:20).

Example 52: Allyl {[(1S, 2R, 3S,4R)-3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-2-(1-propen-1-yl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]oxy}acetate

The compound (3.37 g) produced in Example 51 was dissolved in THF (10mL), a 5N aqueous sodium hydroxide solution (5 mL) and methanol (20 mL)were added, and the mixture was stirred at room temperature for 2 hours.To the reaction mixture was added 2N hydrochloric acid, and the extractobtained by extraction with ethyl acetate was washed with water and asaturated saline, dried with anhydrous magnesium sulfate, andconcentrated under reduced pressure to obtain carboxylic acid (3.02 g).The carboxylic acid (3.02 g) was dissolved in DMF (15 mL), potassiumcarbonate (1.60 g) and allyl bromide (1.0 mL) were added, and themixture was stirred at room temperature overnight. To the reactionmixture was added water, and the extract obtained by extraction withhexane/ethyl acetate (1/1) was washed with water and a saturated saline,dried with anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=97:3→80:20) to obtain a titled compound (2.93 g)having the following physical properties.

TLC: Rf 0.50 (hexane:ethyl acetate=80:20).

Example 53 (1): Methyl (2R)-2-{[(1S, 2R, 3S,4R)-3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-2-(1-propen-1-yl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]oxy}-4-pentenoateExample 53 (2): Methyl (2S)-2-{[(1S, 2R, 3S,4R)-3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-2-(1-propen-1-yl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]oxy}-4-pentenoate

Under the argon atmosphere, diisopropylamine (2.0 mL) was dissolved inTHF (16 mL), and the solution was cooled to 0° C. After a 1.66Mn-butyllithiumhexane solution (8.0 mL) was added dropwise, the mixturewas stirred at the same temperature for 30 minutes. After this wascooled to −78° C., and trimethylchlorosilane (2.0 mL) was addeddropwise, a THF (7 mL) solution of the compound (3.28 g) produced inExample 52 was added dropwise. After stirring at −78° C. for 30 minutes,a temperature was raised to room temperature, and the mixture wasstirred for 1 hour. After water was added to the reaction mixture, andthis was stirred for 1 hour, 1N hydrochloric acid was added, and theextract obtained by extraction with ethyl acetate was washed with waterand a saturated saline, dried with anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (40 mL), methanol (4 mL), and a 2.0Mtrimethylsilyldiazomethanehexane solution (7 mL) were added, and themixture was stirred at room temperature for 1 hour. After the reactionmixture was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography (hexane:ethylacetate=97:3→80:20) to obtain an Example compound 53 (1) (1.26 g) and anExample compound 53 (2) (1.16 g) having the following physical propertyvalues.

TLC: Rf 0.42 (hexane:ethyl acetate=86:14) (compound of Example 53 (1));

TLC: Rf 0.36 (hexane:ethyl acetate=86:14) (compound of Example 53 (2)).

Example 54: Methyl (2R, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)-3,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-2-carboxylate

The compound (1.26 g) produced in Example 53 (1) was dissolved indichloromethane (30 mL), a Schrock's catalyst (0.44 g) was added, andthe mixture was stirred at room temperature overnight. After thereaction mixture was concentrated under reduced pressure, the residuewas purified by silica gel column chromatography (hexane: ethylacetate=95:5→75:25) to obtain a titled compound (0.95 g) having thefollowing physical property values.

TLC: Rf 0.48 (hexane:ethyl acetate=75:25).

Example 55: [(2R, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)-3,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-2-yl]methanol

After lithium aluminum hydride (84 mg) was suspended in THF (2 mL), thesuspension was cooled to 0° C., a THF (3 mL) solution of the compound(0.95 g) produced in Example 54 was added dropwise, and the mixture wasstirred at 0° C. for 15 minutes. After water was added to the reactionmixture, the extract obtained by addition of 1N hydrochloric acid andextraction was washed with water, an aqueous saturated sodiumbicarbonate solution and a saturated saline, dried with anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=60:40→40:60) to obtain a titled compound (793 mg) having thefollowing physical property values.

TLC: Rf 0.43 (hexane:ethyl acetate=50:50).

Example 56: 2-propanyl (2E)-3-[(2R, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)-3,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-2-yl]acrylate

The compound (165 mg) produced in Example 55 was dissolved in DMSO (2mL), a Wittig reagent (carboisopropoxymethylenetriphenylphosphorane, 218mg) and 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (IBX, 168 mg) wereadded, and the mixture was stirred at 50° C. for 5 hours. To thereaction mixture were added ethyl acetate and water, and insolubles werefiltered. The filtrate was extracted with ethyl acetate, and the extractwas washed with an aqueous saturated sodium bicarbonate solution and asaline, dried with anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=97:3→80:20) to obtain a titledcompound (174 mg) having the following physical property values.

TLC: Rf 0.50 (hexane:ethyl acetate=80:20).

Example 57: 2-propanyl 3-[(2R, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-2-yl]propanoate

The compound (174 mg) produced in Example 56 was dissolved in 2-propanol(2 mL), sodium bicarbonate (20 mg) and 10% palladium carbon (20 mg) wereadded, and the mixture was stirred at room temperature for 1 hour underthe hydrogen atmosphere. The filtrate obtained by filtering the reactionmixture with Celite (trade name) was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=97:3→80:20) to obtain a titledcompound (150 mg) having the following physical property values.

TLC: Rf 0.50 (hexane:ethyl acetate=80:20).

Example 58: 2-propanyl 3-[(2R, 5aR, 6S, 7R,8aS)-6-(hydroxymethyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-2-yl]propanoate

To the compound (143 mg) produced in Example 57 was added 1 mL of 1mol/L tetrabutylammonium fluoride (THF solution), and the mixture wasstirred at room temperature overnight. After the reaction mixture wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography (hexane:ethyl acetate=60:40→20:80) to obtain atitled compound (98 mg) having the following physical property values.

TLC: Rf 0.32 (hexane:ethyl acetate=50:50).

Example 59: 2-propanyl 3-{(2R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-2-yl}propanoate

The compound produced in Example 58 was subjected to the same objectiveoperations as those of Example 13→Example 14→Example 15→Example 16 (1)to obtain a titled compound having the following physical propertyvalues.

TLC: Rf 0.32 (hexane:ethyl acetate=1:3);

¹H-NMR (300 MHz, CDCl₃): δ 7.27-7.31, 6.89-6.99, 5.59-5.72, 4.93-5.05,4.49-4.55, 4.21, 3.99, 3.88, 3.69-3.83, 2.55, 2.19-2.44, 1.45-1.88,1.23.

Example 60: [(2S, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)-3,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-2-yl]methanol

Using the compound produced in Example 53 (2), this compound wassubjected to the same objective operations as those of Example54→Example 55 to obtain a titled compound having the following physicalproperty values.

TLC: Rf 0.58 (hexane:ethyl acetate=50:50).

Example 61: 2-Propanyl 3-{(2S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-2-yl}propanoate

Using the compound produced in Example 60, this compound was subjectedto the same objective operations as those of Example 56→Example57→Example 58→Example 59 to obtain a titled compound having thefollowing physical property values.

TLC: Rf 0.34 (hexane:ethyl acetate=1:3);

¹H-NMR (300 MHz, CDCl₃): δ 7.27-7.32, 6.90-7.00, 5.59-5.72, 4.94-5.06,4.49-4.55, 3.93-4.01, 3.88, 3.69-3.79, 3.17-3.25, 2.52, 2.27-2.46,2.06-2.19, 1.65-1.84, 1.26-1.49, 1.23.

Example 62: [(2R, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)-3,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-2-yl]methylmethanesulfonate

Under the argon atmosphere, the compound (207 mg) produced in Example 55was dissolved in dichloromethane (2 mL), and the solution was cooled to0° C. Triethylamine (0.14 mL) and methanesulfonyl chloride (0.040 mL)were added, and the mixture was stirred at 0° C. for 15 minutes. To thereaction mixture was added water, and the extract obtained by extractionwith ethyl acetate was washed with water and a saturated saline, driedwith anhydrous magnesium sulfate, and concentrated under reducedpressure to obtain a titled compound (273 mg) having the followingphysical property values.

TLC: Rf 0.40 (hexane:ethyl acetate=67:33).

Example 63: [(2R, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)-3,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-2-yl]acetonitrile

The compound (273 mg) produced in Example 62 was dissolved in DMSO (1mL), sodium cyanide (55 mg) was added, and the mixture was stirred at80° C. overnight. To the reaction mixture was added water, and theextract obtained by extraction with ethyl acetate was washed with waterand a saturated saline, dried with anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=90:10-70:30) to obtain atitled compound (205 mg) having the following physical property values.

TLC: Rf 0.55 (hexane:ethyl acetate=75:25).

Example 64: 2-propanyl (2E)-3-[(2R, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)-3,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-2-yl]acrylate

The compound (195 mg) produced in Example 63 was dissolved in toluene (4mL), and the solution was cooled to −15° C. A 1M toluene solution (0.8mL) of diisobutylaluminum hydride was added, and the mixture was stirredat the same temperature for 1 hour and 30 minutes. To the reactionmixture was added an aqueous saturated ammonium chloride solution, andthe extract obtained by extraction with ethyl acetate was washed with 1Nhydrochloric acid, an aqueous saturated sodium bicarbonate solution,water and a saturated saline, dried with anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was dissolved indichloromethane (2 mL), phosphorane (250 mg) was added, and the mixturewas stirred at room temperature overnight. After the reaction mixturewas concentrated under reduced pressure, the residue was purified bysilica gel column chromatography (hexane:ethyl acetate=95:5→75:25) toobtain a titled compound (39 mg) having the following physical propertyvalues.

TLC: Rf 0.46 (hexane:ethyl acetate=80:20).

Example 65: 2-propanyl 4-{(2R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-2-yl}butanoate

Using the compound produced in Example 64, this compound was subjectedto the same objective operations as those of Example 56→Example57→Example 58→Example 59 to obtain a titled compound having thefollowing physical property values.

TLC: Rf 0.36 (hexane:ethyl acetate=1:3);

¹H-NMR (300 MHz, CDCl₃): δ 7.26-7.31, 6.89-6.99, 5.60-5.72, 4.93-5.06,4.50-4.55, 4.17-4.24, 3.99, 3.88, 3.70-3.82, 2.56-2.61, 2.21-2.34,1.51-1.78, 1.26-1.37, 1.23.

Example 66: 2-propanyl 4-{(2S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-2-yl}butanoate

Using the compound produced in Example 60, this compound was subjectedto the same objective operations as those of Example 62→Example63→Example 64→Example 56→Example 57→Example 58→Example 59 to obtain atitled compound having the following physical property values.

TLC: Rf 0.42 (hexane:ethyl acetate=1:3);

¹H-NMR (300 MHz, CDCl₃): δ 7.26-7.31, 6.89-6.99, 5.58-5.72, 4.93-5.05,4.48-4.55, 3.97-4.03, 3.87, 3.69-3.77, 3.13-3.22, 2.52-2.59, 2.38-2.47,2.23-2.29, 2.11-2.19, 1.28-1.84, 1.22.

Example 67 (1) to Example 67 (4)

Using the compounds produced in Example 59, Example 61, Example 65 andExample 66, these compounds were subjected to the same objectiveoperations as those of Example 17 (1) to obtain the following Examplecompounds.

Example 67 (1): 3-{(2R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-2-yl}propanoicacid

TLC: Rf 0.36 (chloroform:methanol=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.24-7.30, 6.89-6.98, 5.54-5.70, 4.48, 4.19,3.95, 3.69-3.85, 2.19-2.54, 1.47-1.93.

Example 67 (2): 3-{(2S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahycro-2H-cyclopenta[b]oxepin-2-yl}propanoicacid

TLC: Rf 0.39 (chloroform:methanol=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.24-7.30, 6.88-6.98, 5.56-5.67, 4.45-4.52,3.86-4.02, 3.67-3.76, 3.20-3.29, 2.33-2.52, 2.09-2.18, 1.63-1.86,1.22-1.48.

Example 67 (3): 4-{(2R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-2-yl}butanoicacid

TLC: Rf 0.37 (chloroform:methanol=5:1);

¹H-NMR (300 MHz, CD₃OD): δ 7.21-7.26, 6.87-6.93, 5.56-5.69, 4.38-4.44,4.21-4.29, 3.84-4.00, 3.65-3.77, 2.27-2.36, 2.07-2.17, 1.50-1.84,1.28-1.40.

Example 67 (4): 4-{(2S, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-2-yl}butanoicacid

TLC: Rf 0.42 (chloroform:methanol=5:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.25-7.30, 6.88-6.98, 5.56-5.69, 4.46-4.53,3.86-4.02, 3.67-3.75, 3.14-3.23, 2.40-2.49, 2.35, 2.09-2.18, 1.24-1.84.

Example 68: 4-{(3S, 5aR, 6R, 7R,8aS)-6-[(1E)-4-(3-chlorophenoxy)-3-oxo-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

The compound (102 mg) produced in Example 17 (3) was dissolved inmethylene chloride (2 mL) and acetone (1.5 mL), manganese dioxide (613mg) was added, and the mixture was stirred at 50° C. for 4 hours.Manganese dioxide was removed with Celite (trade name), followed bywashing with chloroform-acetone. After the solvent was concentratedunder reduced pressure, the resulting residue was purified with a PLCglass plate (20×20 cm, silica gel 60 F₂₅₄, 0.5 mm,chloroform:methanol=19:1) to obtain a titled compound (7.8 mg) havingthe following physical property values.

TLC: Rf 0.24 (chloroform:methanol=19:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.96-1.22, 1.36-1.51, 1.51-1.72, 1.84-2.00,2.15-2.31, 2.43-2.55, 2.99, 3.81, 3.96-4.10, 4.93, 6.37, 6.81-7.00,7.19-7.29.

Example 68 (1): 4-{(3S, 5aR, 6R, 7R,8aS)-6-[(1E)-4-(2,5-difluorophenoxy)-3-oxo-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

Using the compound produced in Example 17 (25), this compound wassubjected to the same objective operations as those of Example 68 toobtain the following Example compound.

TLC: Rf 0.42 (dichloromethane:methanol=10:1);

¹H-NMR (CD₃OD): δ 0.96-1.25, 1.36-1.75, 1.84-2.03, 2.15-2.33, 2.50,2.99, 3.81, 3.96-4.11, 5.00, 6.37, 6.67, 6.79, 6.91, 7.11.

Example 69: (5aR, 6S, 7R,8aS)-6-({[(dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-3-[4-oxo-4-(2-propanyloxy)butyl]octahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate

To a methylene chloride (2.3 mL) solution of the compound (500 mg)produced in Example 10 were added triethylamine (0.246 mL),4-phenylbenzoyl chloride (303 mg) and dimethylaminopyridine (2 mg) underice-cooling and the argon atmosphere, and the mixture was stirred atroom temperature for 6 hours. Further, triethylamine (0.123 mL) and4-phenylbenzoyl chloride (151 mg) were added, and the mixture wasstirred at room temperature overnight. After completion of the reaction,the reaction mixture was diluted with ethyl acetate, water was added,and this was extracted with ethyl acetate. The organic layer was washedwith an aqueous saturated sodium bicarbonate solution, water and asaturated saline. After drying with anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure, the precipitatedcrystal was removed with MTBE, and the filtrate was concentrated underreduced pressure. The resulting residue was purified by preparativechromatograph (Hiflash-SI, size L, hexane:ethylacetate=100:0→9:1-4:1→3:2) manufactured by Yamazen Corporation to obtaina titled compound (641 mg) having the following physical propertyvalues.

TLC: Rf 0.64 (hexane:ethyl acetate=3:1).

Example 70: (3S, 5aR, 6S, 7R,8aS)-6-(hydroxymethyl)-3-[4-oxo-4-(2-propanyloxy)butyl]octahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate

To a THF (0.5 mL) solution of the compound (640 mg) produced in Example69 was added a 1M THF solution (2.1 mL) of tetrabutylammonium fluorideat room temperature, and the mixture was stirred for 2 hours. Aftercompletion of the reaction, the reaction mixture was diluted with ethylacetate, and the reaction was stopped with an ice-cooled aqueoussaturated ammonium chloride solution. This was extracted with ethylacetate, the organic layer was washed with water and a saturated saline,and dried with anhydrous sodium sulfate, and the solvent wasconcentrated under reduced pressure. The resulting residue was purifiedby preparative chromatograph (Hiflash-SI, Size L, hexane: ethylacetate=85:15→7:3→1:1→3:7) manufactured by Yamazen Corporation to obtaina titled compound (214 mg) having the following physical propertyvalues.

TLC: Rf 0.30 (hexane:ethyl acetate=2:1).

Example 71: (3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-(tetrahydro-2H-pyran-2-yloxy)-1-buten-1-yl]-3-[4-oxo-4-(2-propanyloxy)butyl]octahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate

Using the compound produced in Example 70, this compound was subjectedto the same objective operations as those of Example 13→Example14→Example 15→Example 11 to obtain a titled compound having thefollowing physical property values.

TLC: Rf 0.58 (hexane:ethyl acetate=2:1).

Example 72: 2-propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-(tetrahydro-2H-pyran-2-yloxy)-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

To a 2-propanol (5 mL) solution of the compound (950 mg) produced inExample 71 was added lithium isopropoxide (2.0M THF solution, 2.3 mL),and the reaction mixture was stirred at 50° C. for 5 hours. The reactionmixture was cooled to 0° C., and poured into a water-ethyl acetate mixedsolution which had been similarly cooled to 0° C., and the organic layerwas washed with water and a saturated saline, dried with magnesiumsulfate, and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (hexane:ethylacetate=1:1→only ethyl acetate) to obtain a titled compound (530 mg)having the following physical property values.

TLC: Rf 0.26 (hexane:ethyl acetate=1:1).

Example 73: 2-propanyl 4-[(3S, 5aR, 6R, 7S, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-(tetrahydro-2H-pyran-2-yloxy)-1-buten-1-yl]-7-(formyloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

To a THF (0.3 mL) solution of the compound (29 mg) produced in Example72 were added triphenylphosphine (27 mg), formic acid (4 μL) and atoluene solution of diethyl azodicarboxylate (47 μL, 2.2 mol/L) at −15°C., and the reaction mixture was stirred at 0° C. for 1.5 hours.Further, triphenylphosphine (27 mg), formic acid (4 μL) and a toluenesolution of diethyl azodicarboxylate (47 μL, 2.2 mol/L) were added at 0°C., and the reaction mixture was stirred at room temperature for 2hours. To the reaction mixture was added an aqueous saturated bakingsoda solution, and this was extracted with ethyl acetate. The organiclayer was washed with water and an aqueous saturated sodium chloridesolution, dried with anhydrous sodium sulfate, and concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=8:2-5:5) to obtain a titledcompound (10 mg) having the following physical property values.

TLC: Rf 0.32 (hexane:ethyl acetate=2:3).

Example 74: 2-propanyl 4-[(3S, 5aR, 6R, 7S, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-(tetrahydro-2H-pyran-2-yloxy)-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

To a 2-propanol (0.35 mL) solution of the compound (10 mg) produced inExample 73 was added potassium carbonate (3 mg) at 0° C., and thereaction mixture was stirred at 40° C. for 1 hour. To the reactionmixture was added an aqueous saturated ammonium chloride solution, andthis was extracted with ethyl acetate. The organic layer was washed witha saturated saline, dried with anhydrous magnesium sulfate, andconcentrated under reduced pressure to obtain a titled compound (8 mg)having the following physical property values.

TLC: Rf 0.39 (hexane:ethyl acetate=1:1).

Example 75: 2-propanyl 4-{(3S, 5aR, 6R, 7S, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

Using the compound produced in Example 74, this compound was subjectedto the same objective operations as those of Example 16 (1) to obtain atitled compound having the following physical property values.

TLC: Rf 0.47 (hexane:ethyl acetate=1:4);

¹H-NMR (300 MHz, CDCl₃): δ 7.00, 6.71, 6.60, 5.90, 5.63, 4.99, 4.56,4.28, 4.18, 4.08-3.88, 2.97, 2.78, 2.15-2.00, 1.95-0.95.

Example 76: 4-{(3S, 5aR, 6R, 7S, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

Using the compound produced in Example 75, this compound was subjectedto the same objective operations as those of Example 17 (1) to obtain atitled compound having the following physical property values.

TLC: Rf 0.28 (dichloromethane:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 7.08-6.90, 6.78-6.52, 5.90, 5.63, 4.57, 4.29,4.22-3.85, 2.97, 2.40-2.20, 2.13, 1.98-1.80, 1.80-1.50, 1.45-0.95.

Example 77: (1R, 2R, 3S,4R)-2-allyl-3-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol

Using the compound produced in Example 3, this compound was subjected tothe same objective operations as those of Example 73 to obtain a titledcompound having the following physical properties.

TLC: Rf 0.59 (hexane:ethyl acetate=2:1).

Example 78: 2-propanyl 4-[(5aR, 6S, 7R,8aR)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

Using the compound produced in Example 77, this compound was subjectedto the same objective operations as those of Example 4→Example 5→Example6→Example 7→Example 8 to obtain a titled compound having the followingphysical property values.

TLC: Rf 0.39 (hexane:ethyl acetate=4:1).

Example 79: 2-propanyl 4-{(5aR, 6R, 7R, 8aR)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

Using the compound produced in Example 78, this compound was subjectedto the same objective operations as those of Example 12→Example13→Example 14→Example 15→Example 16 (1) to obtain a titled compoundhaving the following physical property values.

TLC: Rf 0.52 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.19-1.33, 1.43-1.58, 1.65-1.79, 1.86-2.16,2.16-2.34, 2.59, 3.77, 3.92, 3.97-4.19, 4.51-4.62, 5.01, 5.58-5.82,6.89-7.04, 7.25-7.36.

Example 80: 4-{(5aR, 6R, 7R, 8aR)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]-5,5a,6,7,8,8a-hexahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

Using the compound produced in Example 79, this compound was subjectedto the same objective operations as those of Example 17 (1) to obtain atitled compound having the following physical property values.

TLC: Rf 0.64 (dichloromethane:methanol=7:1);

¹H-NMR (300 MHz, CD₃OD): δ 1.25-1.49, 1.57-1.76, 1.87-2.12, 2.18-2.34,3.77, 3.89-4.19, 4.44, 5.57-5.77, 6.84-7.01, 7.21-7.33.

Example 81: 2-propanyl 4-{(5aR, 6R, 7R, 8aR)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

Using the compound produced in Example 78, this compound was subjectedto the same objective operations as those of Example 9→Example10→Example 11→Example 12→Example 13→Example 14→Example 15→Example 16 (1)to obtain a titled compound having the following physical propertyvalues.

TLC: Rf 0.46 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.97-2.14, 2.18-2.34, 2.53-2.63, 3.23, 3.44,3.71-4.18, 4.49-4.61, 4.93-5.09, 5.58-5.82, 6.88-7.04, 7.24-7.36.

Example 81 (1): 2-propanyl 4-{(5aR, 6R, 7R, 8aR)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

Using the compound produced in Example 78, and usingdimethyl-(3-phenoxy-2-oxopropyl)-phosphonate or a correspondingphosphonic acid salt in place of it, these substances were subjected tothe same objective operations as those of Example 81 to obtain a titledcompound having the following physical properties.

TLC: Rf 0.52 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 1.00-1.91, 1.91-2.13, 2.22-2.33, 2.59-2.68,3.23, 3.44, 3.73-4.19, 4.52-4.63, 4.95-5.07, 5.56-5.83, 6.57-6.68,6.68-6.78, 6.97-7.10.

Example 82 to Example 82 (1)

Using the compounds produced in Example 81 or Example 81 (1), thiscompound was subjected to the same objective operations as those ofExample 17 (1) to obtain the following Example compounds.

Example 82: 4-{(5aR, 6R, 7R, 8aR)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.53 (dichloromethane:methanol=7:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.99-2.04, 2.21-2.33, 3.20-3.46, 3.73-4.03,4.43, 5.56-5.77, 6.86-5.77, 6.86-6.95, 7.20-7.30.

Example 82 (1): 4-{(5aR, 6R, 7R, 8aR)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

TLC: Rf 0.47 (dichloromethane:methanol=7:1);

¹H-NMR (300 MHz, CD₃OD): δ 1.00-2.06, 2.22-2.33, 3.20-3.47, 3.74-3.86,3.88-4.02, 4.45, 5.54-5.79, 6.57-6.68, 6.68-6.96, 7.01-7.13.

Example 83: 4-[(3S, 5aR, 6R, 7R,8aS)-6-(3,3-difluoro-4-phenoxybutyl)-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl]butanoicacid

Using the compound produced in Example 30, this compound was subjectedto the same objective operations as those of Example 18→Example 19 toobtain a titled compound having the following physical property values.

TLC: Rf 0.51 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 7.35-7.29, 7.02, 6.95-6.91, 4.13, 4.04, 3.97,3.74, 2.93, 2.34, 2.28-2.03, 1.95-1.51, 1.22-1.00.

Example 84: [(3S, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]methylmethanesulfonate

To a methylene chloride (300 mL) solution of the compound (40.7 g)produced in Example 23 were sequentially added triethylamine (27.36 mL)and mesyl chloride (7.98 mL) under ice-cooling, and the mixture wasstirred for 1 hour. The reaction solution was poured into ice-water (300mL), and this was extracted with ethyl acetate. The extract was washedwith water (100 mL) and a saturated saline (100 mL), and dried withanhydrous sodium sulfate. Concentration of the solvent under reducedpressure afforded a titled compound (50.2 g) having the followingphysical property values.

TLC: Rf 0.71, 0.63 (methylene chloride: ethyl acetate=2:1).

Example 85: [(3R, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]acetonitrile

To a DMSO (250 mL) solution of the compound (50.2 g) produced in Example84 was added sodium cyanide (8.18 g) at room temperature, and themixture was stirred at 70° C. overnight. The reaction solution waspoured into ice water (750 mL), and this was extracted with ethylacetate. The organic layer was washed with water (200 mL) and asaturated saline (200 mL), and dried with anhydrous sodium sulfate. Thesolvent was concentrated under reduced pressure, and the resultingresidue was purified by preparative chromatograph (Hiflash-SI, Size 5L×2, hexane:ethyl acetate=90:10→2:1→1:1) manufactured by YamazenCorporation to obtain a titled compound (36.4 g) having the followingphysical property values.

TLC: Rf 0.42 (hexane:ethyl acetate=2:1).

Example 86: [(3R, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]acetaldehyde

Under the argon atmosphere, a toluene (350 mL) solution of the compound(29.4 g) produced in Example 85 was cooled to −18° C., and a 1M toluenesolution (103 mL) of DIBAL was added dropwise over 40 minutes. Thereaction solution was diluted with MTBE (300 mL), an aqueous saturatedsodium tartrate solution (50 mL) was added under ice-cooling, themixture was stirred for a while, thereafter, ice-cooled hydrochloricacid (1N, 300 mL) was added, and this was extracted with ethyl acetate.The organic layer was washed with an aqueous saturated ammonium chloridesolution, water and a saturated saline, and dried with anhydrous sodiumsulfate. Concentration of the solvent under reduced pressure afforded atitled compound (31.3 g) having the following physical property values.

TLC: Rf 0.45 (hexane:ethyl acetate=3:1).

Example 87: 2-propanyl (2E)-4-[(3R, 5aR, 6S, 7R,8aS)-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]-2-butenoate

To a methylene chloride (422 mL) solution of the compound (38.0 g)produced in Example 86 was added isopropyl(triphenylphosphoranylidene)acetate (45.93 g) at room temperature, and the mixture was stirred atroom temperature overnight. After completion of the reaction, thesolution was concentrated under reduced pressure, and diethylether-hexane (1:1, 200 mL) were added. After removal of the analysisproduct with a glass filter, the filtrate was concentrated under reducedpressure. The resulting residue was purified by preparativechromatograph (Hiflash-SI, Size 5 L×2, hexane:ethylacetate=100:0→4:1→-7:3) manufactured by Yamazen Corporation to obtain atitled compound (36.0 g) having the following physical property values.

TLC: Rf 0.56, 0.49 (hexane:ethyl acetate=4:1).

Example 88: Ethyl (2E)-4-{(3R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}-2-butenoate

Using the compound produced in Example 87, this compound was subjectedto the same objective operations as those of Example 12→Example13→Example 14→Example 15→Example 16 (1) to obtain a titled compoundhaving the following physical property values.

TLC; Rf 0.46 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.96-1.12, 1.25-1.33, 1.41-1.54, 1.63-2.18,2.45-2.54, 2.69, 2.92-2.30, 3.69-3.78, 3.87-4.23, 4.52-4.55, 5.61-5.74,5.77-5.83, 6.84-7.01, 7.24-7.33.

Example 89: (2E)-4-{(3R, 5aR, 6R, 7R, 8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}-2-butenoicacid

Using the compound produced in Example 88, this compound was subjectedto the same objective operations as those of Example 17 (1) to obtain atitled compound having the following physical property values.

TLC: Rf 0.31 (dichloromethane:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 1.00-1.51, 1.68-2.14, 2.45-2.54, 2.93-3.00,3.69-3.77, 3.87-4.07, 4.52-4.54, 5.65-5.67, 5.79-5.84, 6.91-7.04,7.27-7.32.

Example 90: 4-{(3S, 5aR, 6R, 7S, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-fluorooctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

Using the compound (100 mg) produced in Example 72, this compound wassubjected to the same objective operations as those of Example30→Example 31→Example 32 to obtain a titled compound (4 mg) having thefollowing physical property values.

TLC: Rf 0.52 (dichloromethane:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.85-2.62, 2.96-3.04, 3.92-4.09, 4.24-4.31,4.55-4.61, 4.84-4.86, 5.02-5.04, 5.60-5.67, 5.85-5.93, 6.58-6.66,6.70-6.76, 6.99-7.08.

Example 91: Ethyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

To a DMF (0.3 mL) solution of the compound (50 mg) produced in Example17 (25) were added ethyl iodide (21 mg) and potassium carbonate (19 mg),and the reaction mixture was stirred at 50° C. for 30 minutes. Thereaction mixture was poured into water, and this was extracted withMTBE. Herein, the aqueous layer was made acidic (pH=4) with 1Nhydrochloric acid, and extracted with ethyl acetate, and the organiclayer was washed with water and a saturated saline, dried with magnesiumsulfate, and concentrated under reduced pressure to recover an unreactedraw material (15 mg). The reaction was tried on the recovered rawmaterial with the aforementioned reagents (ethyl iodide 12 mg, potassiumcarbonate 6 mg), the mixture was stirred at 50° C. for 1 hour, thereaction mixture was poured into water, and this was extracted withMTBE. The organic layer was washed with water and an aqueous saturatedsodium chloride solution, dried with sodium sulfate, and concentratedunder reduced pressure, and the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=1:1→-0:100) to obtain atitled compound (21 mg) having the following physical property values.

TLC: Rf 0.53 (dichloromethane:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.94-1.30, 1.40-1.95, 2.09-2.31, 2.45-2.54,2.71-2.73, 2.89-2.97, 3.70-3.79, 3.90-4.17, 4.53-4.60, 5.59-5.74,6.58-6.66, 6.69-6.76, 6.99-7.08.

Example 91 (1): 3-hydroxypropyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

Using the compound produced in Example 17 (25), and using3-bromo-1-propanol in place of ethyl iodide, these substances weresubjected to the same objective operations as those of Example 91 toobtain a titled compound having the following physical property values.

TLC: Rf 0.38 (dichloromethane:acetone=1:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.90-1.20, 1.40-1.94, 2.08-2.17, 2.28-2.33,2.45-2.54, 2.89-2.96, 3.67-3.80, 3.91-4.07, 4.22-4.26, 4.52-4.58,5.59-5.74, 6.58-6.66, 6.69-6.75, 6.99-7.07.

Example 92: (3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-3-(4-hydroxybutyl)octahydro-2H-cyclopenta[b]oxepine-7-ol

To a THF (1.4 mL) solution of the compound (25 mg) produced in Example91 was added lithium aluminum hydride (6 mg) at 0° C., and the reactionmixture was stirred as it was for 1 hour. To the reaction mixture wasadded an aqueous saturated sodium sulfate solution, and the mixture wasfiltered with Celite (trade name), and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (ethyl acetate-dichloromethane:methanol=9:1) to obtain atitled compound (22 mg) having the following physical property values:

TLC: Rf 0.24 (ethyl acetate);

¹H-NMR (300 MHz, CDCl₃): δ 0.95-1.95, 2.01-2.18, 2.45-2.54, 2.62-2.64,2.89-2.97, 3.62-3.80, 3.90-4.09, 4.54-4.61, 5.60-5.75, 6.58-6.66,6.69-6.76, 6.99-7.08.

Example 93: 4-{(3 S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}-N-ethylbutaneamide

To a THF (0.2 mL) solution of the compound (10 mg) produced in Example17 (25) were added4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (7mg) and an aqueous ethylamine solution (12M, 19 μL), and the reactionmixture was stirred at room temperature for 6 hours. The reactionmixture was poured into water, this was extracted with ethyl acetate,and the organic layer was washed with 1N hydrochloric acid, an aqueoussaturated sodium bicarbonate solution, and a saturated saline, driedwith magnesium sulfate, and concentrated under reduced pressure toobtain the residue. The resulting residue was purified by silica gelcolumn chromatography (dichloromethane:methanol=9:1) to obtain a titledcompound (10 mg) having the following physical property values.

TLC: Rf 0.44 (dichloromethane:methanol=9:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.85-1.20, 1.30-1.92, 1.97-2.06, 2.11-2.16,2.39-2.48, 2.92-3.01, 3.14-3.23, 3.62-3.71, 3.96-4.03, 4.41-4.47,5.58-5.71, 6.59-6.67, 6.88-6.95, 7.03-7.12, 7.94.

Example 94: 3-(3-pyridinyl)propanal

To an ethyl acetate (30 mL) solution of 3-(3-pyridyl)propanol (1.5 g)were added dimethyl sulfoxide (15 mL) and triethylamine (9 mL), apyridine sulfur trioxide complex (5.2 g) was added while the mixture wasstirred at 0° C., and the mixture was stirred as it was for 2 hours. Thereaction mixture was concentrated under reduced pressure, and purifiedby silica gel column chromatography (hexane:ethyl acetate=30:70→0:100)to obtain a titled compound (1:1 g) having the following physicalproperty values.

TLC: Rf 0.23 (hexane:ethyl acetate=1:2).

Example 95: (3S, 5aR, 6S, 7R,8aS)-6-[(E)-2-iodovinyl]-3-[4-oxo-4-(2-propanyloxy)butyl]octahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate

To a THF (10 mL) solution of the compound (0.85 g) produced in Example70 was added chromium chloride (1.7 g), a THF (7 mL) solution ofiodoform (1.4 g) was added while the mixture was stirred at 0° C., andthe mixture was stirred as it was for 4 hours. The reaction mixture waspoured into water, this was extracted with ethyl acetate, and theorganic layer was washed with water and a saturated saline, dried withmagnesium sulfate, and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=95:5→75:25) to obtain a titled compound (600 mg)having the following physical property values.

TLC: Rf 0.47 (hexane:ethyl acetate=3:1).

Example 96: (3S, 5aR, 6R, 7R,8aS)-6-[(1E)-3-hydroxy-5-(3-pyridinyl)-1-penten-1-yl]-3-[4-oxo-4-(2-propanyloxy)butyl]octahydro-2H-cyclopenta[b]oxepin-7-yl4-biphenylcarboxylate

To a THF (10 mL) solution of the compound (590 mg) produced in Example95 and the compound (258 mg) produced in Example 94 were added chromiumchloride (470 mg) and nickel chloride (2.5 mg), and the mixture wasstirred at room temperature overnight. The reaction mixture was pouredinto water, and this was extracted with ethyl acetate. An aqueoussaturated sodium bicarbonate solution was added to both of the aqueouslayer and the organic layer, respectively, both were stirred, andcombined, filtered with Celite (trade name), and separated into theaqueous layer and the organic layer again, and the resulting organiclayer was dried with magnesium sulfate, and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=30:70→0:100) to obtain a titledcompound (210 mg) having the following physical property values.

TLC: Rf 0.38 (ethyl acetate).

Example 97: 2-propanyl 4-{(3S, 5aR, 6R, 7R,8aS)-7-hydroxy-6-[(1E)-3-hydroxy-5-(3-pyridinyl)-1-penten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

To a 2-propanol (0.4 mL) solution of the compound (210 mg) produced inExample 96 was added lithium isopropoxide (2.0M THF solution, 0.33 mL),and the reaction mixture was stirred at 50° C. for 4 hours. The reactionmixture was cooled to 0° C., and poured into a water-ethyl acetate mixedsolution which had been similarly cooled to 0° C., and the organic layerwas washed with water and a saturated saline, dried with magnesiumsulfate, and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography(dichloromethane:methanol=100:0→90:10) to obtain a titled compound (108mg) having the following physical property values.

TLC: Rf 0.53 (dichloromethane:methanol=9:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.93-1.29, 1.39-1.93, 2.04-2.14, 2.22-2.27,2.42-2.52, 2.63-2.82, 2.88-2.96, 3.65-3.75, 3.92-4.14, 4.94-5.06,5.42-5.67, 7.20-7.24, 7.52-7.54, 8.44-8.46.

Example 98: 4-{(3S, 5aR, 6R, 7R,8aS)-7-hydroxy-6-[(1E)-3-hydroxy-5-(3-pyridinyl)-1-penten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

Using the compound produced in Example 97, this compound was subjectedto the same objective operations as those of Example 17 (1) to obtain atitled compound having the following physical property values.

TLC: Rf 0.64 (dichloromethane:methanol=4:1);

¹H-NMR (300 MHz, CD₃OD): δ 0.97-2.04, 2.24-2.29, 2.37-2.47, 2.70-2.77,2.94-3.02, 3.58-3.68, 3.96-4.05, 5.54-5.60, 7.33-7.38, 7.71-7.74,8.33-8.40.

Example 99: 5-[(3-phenoxypropyl)thio]-1-phenyl-1H-tetrazole

3-phenoxypropyl bromide (1.53 g) was dissolved in acetone (9 mL),1-phenyl-5-mercapto-1H-tetrazole (1.27 g) and potassium carbonate (985mg) were added, and the mixture was stirred at room temperature for 3hours. To the reaction solution was added water, and the extractobtained by extraction with ethyl acetate was washed with water and asaturated saline, dried with anhydrous magnesium sulfate, andconcentrated under reduced pressure to obtain a titled compound (2.23 g)having the following physical property values.

TLC: Rf 0.62 (hexane:ethyl acetate=67:33).

Example 100: 5-[(3-phenoxypropyl)sulfonyl]-1-phenyl-1H-tetrazole

The compound (2.23 g) produced in Example 99 was dissolved indichloromethane (10 mL), m-chloroperbenzoic acid (4.5 g) was added, andthe mixture was stirred at room temperature overnight. To the reactionsolution was added a 5% aqueous sodium sulfide solution, and the extractobtained by extraction with ethyl acetate was washed with an aqueoussaturated sodium bicarbonate solution, water and a saturated saline. Theorganic layer was dried with anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=85:15→65:35) to obtain atitled compound (1.78 g) having the following physical property values.

TLC: Rf 0.59 (hexane:ethyl acetate=67:33).

Example 101: 2-propanyl 4-[(3S, 5aR, 6R, 7R,8aS)-6-[(1E)-4-phenoxy-1-buten-1-yl)-7-(tetrahydro-2H-pyran-2-yloxy)octahydro-2H-cyclopenta[b]oxepin-3-yl]butanoate

Under the argon atmosphere, the compound (165 mg) produced in Example100 was dissolved in DME (2 mL), the solution was cooled to −78° C., anda 0.5M potassium hexamethyldisilazane/toluene solution (0.90 mL) wasadded. After the mixture was stirred at −78° C. for 20 minutes, a DME(1.5 mL) solution of the compound produced in Example 13 was addeddropwise, and the mixture was stirred at the same temperature for 10minutes. After a temperature of the reaction solution was raised to 0°C., water was added, and the extract obtained by extraction with ethylacetate was washed with water and a saturated saline, dried withanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=90:10→65:35) to obtain a titled compound (177 mg)having the following physical property values.

TLC: Rf 0.58 (hexane:ethyl acetate=67:33).

Example 102: 2-propanyl 4-{(3S, 5aR, 6R, 7R,8aS)-7-hydroxy-6-[(1E)-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

Using the compound produced in Example 101, this was subjected to thesame objective operations as those of Example 16 (1) to obtain a titledcompound having the following physical property values.

TLC: Rf 0.52 (hexane:ethyl acetate=33:67);

¹H-NMR (300 MHz, CDCl₃): δ 7.32-7.25, 6.97-6.88, 5.62, 5.37, 5.01,4.08-3.93, 3.68, 2.92, 2.57-2.43, 2.25, 2.06, 1.91, 1.82-1.40, 1.24,1.18-0.93.

Example 103: 4-{(3S, 5aR, 6R, 7R,8aS)-7-hydroxy-6-[(1E)-4-phenoxy-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoicacid

Using the compound produced in Example 102, this compound was subjectedto the same objective operations as those of Example 17 (1) to obtain atitled compound having the following physical property values.

TLC: Rf 0.69 (ethyl acetate:methanol=9:1);

¹H-NMR (300 MHz, DMSO-d₆): δ 11.98, 7.27, 6.93-6.88, 5.51-5.32, 4.61,3.99-3.93, 3.90-3.81, 3.47, 2.84, 2.42, 2.26, 2.15, 1.87-1.74,1.65-1.20, 1.10-0.86.

Example 104: 4-(nitrooxy)butylamine nitrate

Fuming nitric acid (1.5 mL) was added dropwise to acetic acid (25 mL)which had been cooled to an inner temperature of −8° C. while an innertemperature of 0° C. or lower was maintained. After the mixed solutionwas stirred for 10 minutes, 4-amino-1-butanol (3.1 mL) was addeddropwise while an inner temperature of 0° C. or lower was maintained.After the mixture was stirred for 10 minutes, a temperature was raisedto room temperature with a water bath. After the mixture was stirred for10 minutes, diethyl ether (100 mL) was added, and this was concentratedunder reduced pressure. To the resulting concentrated material was addeddiethyl ether (100 mL), the mixture was stirred, and the supernatant wasremoved. The resulting residue was concentrated under reduced pressureto obtain a titled compound (6.31 g) having the following physicalproperty values.

¹H-NMR (300 MHz, DMSO-d₆): δ 1.44-1.82, 2.68-2.93, 4.53, 7.20-8.15.

Example 105: 4-[(4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoyl)amino]butylnitrate

To a DMF solution (1 mL) of the compound (68 mg) produced in Example 104were added sequentially 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (87 mg) and triethylamine (95 μL) at room temperature.After the mixture was stirred overnight, the solution was diluted withethyl acetate, and washed with 1N hydrochloric acid two times, withwater once, and with a saturated saline once. This was dried withanhydrous sodium sulfate, and concentrated under reduced pressure. Theresulting crude purified product was purified with a column apparatus(Hi-Flash M, ethyl acetate→ethyl acetate:methanol=7:3). Furtherpurification with preparative TLC (toluene:acetone=1:1) and preparativeTLC (ethyl acetate:methanol=5:1) afforded a titled compound (7.5 mg)having the following physical property values.

TLC: Rf 0.72 (ethyl acetate:methanol=7:1);

¹H-NMR (300 MHz, CDCl₃): δ 0.83-1.54, 1.54-1.97, 1.97-2.43, 2.49,2.71-3.01, 3.30, 3.74, 3.89-4.10, 4.48, 4.52-4.60, 5.42-5.55, 5.58-5.75,6.62, 6.72, 7.03.

[Process for Producing Crystal of the Present Invention Compound]

In the present invention, each crystal form of the Example compounds canbe produced by the methods described in Examples, or methods accordingto them.

Physical property data of each crystal described in Examples wereobtained under the following measurement conditions.

[1] Powder X-Ray Diffraction Spectra <Measurement Condition>

Apparatus: BRUKER D8 DISCOVER with GADDS manufactured by BRUKER axs

Target: Cu, Filter: None Voltage: 40 kV, Current: 40 mA,

Light exposure: 3 min.

[2] Differential Scanning Calorimetry (DSC) <Measuring Condition>

Apparatus: DSC 822e manufactured by METTLER TOLEDO,Sample amount: 1 to 2 mg,Sample cell: Aluminum pan 40 μL,Nitrogen gas flow rate: 40 mL/min,Temperature raising rate: 0.5, 1, 3, 5 and 10° C./min (25 to 300° C.).

Example A: Crystal of 2-propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate(A-type crystal)

To the compound (1.25 g) produced in Example 16 (3) was added 18.75 mL(15 v/w) of a mixed solvent of 2-propanol-heptane (1:7), and this washeated with an oil bath at 70° C. to dissolve the compound. Atemperature was lowered to 38° C., and the solution was stirred forabout 6.5 hours. After a temperature was returned to room temperature,the solution was stirred for 13.5 hours, and allowed to stand at roomtemperature for 4.5 hours. The resulting crystal was filtered, washedusing 2-propanol-heptane (1:7), and dried under reduced pressure at 50°C. to obtain a titled A-type crystal (1.12 g). Powder X-ray diffractionspectrum of the A-type crystal is shown in FIG. 3, and a differentialscanning calorimetry (DSC) chart is shown in FIG. 4, respectively. Inaddition, a diffraction angle 2 θ and a relative intensity in the powderX-ray diffraction spectrum are shown in the following Table.

TABLE 1 Diffraction angle 2θ (degree) Relative intensity (%) 7.306 12.810.794 72 13.892 21.3 14.325 26 15.431 11.8 15.927 21.4 16.435 20.316.743 15.7 17.327 21.7 18.09 42.9 19.59 17.3 20.204 12.6 21.854 9322.604 100 23.886 42.8 24.341 36.5

The present crystal showed an endothermic peak corresponding to meltingat about 96° C.

Example B: Crystal of 2-propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(3-chlorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate(B-type crystal)

Solidification by concentration afforded the compound (23.6 mg) producedin Example 16 (3). It was seen that, in the resulting crystal, theA-type crystal produced in Example A and its different crystal (B-typecrystal) are present in admixture thereof. The resulting crystal wasanalyzed, its powder X-ray diffraction spectrum is shown in FIG. 5, anda differential scanning calorimetry (DSC) chart is shown in FIG. 6,respectively. In addition, a diffraction angle 20 and a relativeintensity in the powder X-ray diffraction spectrum are shown in thefollowing Table.

Powder X-Ray Diffraction Spectrum:

TABLE 2 Diffraction angle 2θ (degree) Relative intensity (%) 5.453 32.76.427 25.9 9.896 36.8 10.69 18.1 11.472 17.9 14.645 66 15.81 46.8 16.33719.8 17.277 27 17.975 24.6 18.45 26.4 19.009 41.1 19.493 48.1 19.90670.8 21.046 100 21.734 38.9 22.521 42.7 23.765 18.8 24.231 19.1

The present crystal showed an endothermic peak corresponding to meltingat about 93° C.

Example C: Crystal of 2-propanyl 4-{(3S, 5aR, 6R, 7R,8aS)-7-hydroxy-6-[(1E,3R)-3-hydroxy-4-phenoxy-1-buten-1-yl]octahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate

The compound (20.6 mg) produced in Example 16 (1) was dried underreduced pressure at 50° C. for about 1 day to obtain a titled crystalhaving the following physicochemical data. A power X-ray diffractionspectrum of the present crystal is shown in FIG. 7. In addition, adiffraction angle 20 and a relative intensity in the powder X-raydiffraction spectrum are shown in the following Table.

Powder X-Ray Diffraction Spectrum:

TABLE 3 Diffraction angle 2θ (degree) Relative intensity (%) 5.397 216.689 27.3 7.348 13.5 10.772 26.2 13.237 13 14.11 61.1 15.624 38.617.002 15 17.541 19.3 18.492 20.8 19.292 100 20.009 36.8 21.285 33.221.598 35.5 22.009 33.7 23.222 22.4

Example D: Crystal of 2-propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate(A-type crystal)

The compound (1.13 g) produced in Example 16 (25) was placed into aneggplant flask, and 22.6 mL (15 v/w) of a mixed solvent of isopropylacetate-heptane (1:4) was added. The materials were heated with an oilbath at 60° C. to dissolve the compound. The solution was allowed tocool to 45° C., and stirred for 2 hours. The solution was furtherallowed to cool to room temperature, and stirred overnight, and theresulting crystal was filtered, and dried under reduced pressure at 50°C. to obtain a titled A-type crystal. A powder X-ray diffractionspectrum of the A-type crystal is shown in FIG. 8, and a differentialscanning calorimetry (DSC) chart is shown in FIG. 9, respectively. Inaddition, a diffraction angle 2θ and a relative intensity in the powderX-ray diffraction spectrum are shown in the following Table.

Powder X-Ray Diffraction Spectrum:

TABLE 4 Diffraction angle 2θ (degree) Relative intensity (%) 5.597 49.78.421 16.6 8.901 23 11.017 23.4 11.74 12.1 12.127 34.8 12.654 13.113.672 16.9 14.22 91.1 14.683 16 15.247 100 16.431 38 16.828 35.1 17.80520.4 18.767 29.7 19.074 26.5 20.144 35.4 21.344 18.6 21.925 28 23.13118.8 24.538 23.3

The present crystal showed an endothermic peak corresponding to meltingat about 80° C.

Example E: Crystal of 2-propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate(B-type crystal)

To the compound (20 mg) produced in Example 16 (25) was added 0.20 mL(10 v/w) of a mixed solvent of isopropyl acetate-heptane (1:4). Thematerials were heated with an oil bath at 80° C. to dissolve thecompound. After allowing to cool from 80° C. to 25° C. at a rate of 3°C./min, the resulting crystal was filtered, and dried under reducedpressure. It was seen that the A-type crystal produced in Example D andits different crystal (B-type crystal) are present in admixture thereof.The resulting crystal was analyzed, its powder X-ray diffractionspectrum is shown in FIG. 10, and a differential scanning calorimetry(DSC) chart is shown in FIG. 11, respectively. In addition, adiffraction angle 20 and a relative intensity in the powder X-raydiffraction spectrum are shown in the following Table.

Powder X-Ray Diffraction Spectrum:

TABLE 5 Diffraction angle 2θ (degree) Relative intensity (%) 5.531 22.56.442 30.1 8.927 17.1 9.554 16 10.049 17.7 11.708 21.5 12.124 17.812.682 29.6 13.822 21.7 14.496 38.8 15.166 30.8 15.651 78.8 16.015 46.116.858 26.8 17.638 52.8 17.979 55.5 19.006 60.1 19.786 100 21.034 77.621.748 41.5 22.482 42.9 23.744 25 24.571 47.7

The present crystal showed an endothermic peak corresponding to meltingat about 64° C.

Example F: Crystal of 2-propanyl 4-{(3S, 5aR, 6R, 7R, 8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate(C-type crystal)

To the compound (20 mg) produced in Example 16 (25) was added 0.20 mL(10 v/w) of a mixed solvent of isopropyl acetate-heptane (1:4). Thematerials were heated with an oil bath at 80° C. to dissolve thecompound. After allowing to cool from 70° C. to 25° C. at a rate of 3°C./min, the resulting crystal was filtered, and dried under reducedpressure. As a result, it was seen that the A-type crystal produced inExample D and its different crystal (C-type crystal) are present inadmixture thereof. The resulting crystal was analyzed, its powder X-raydiffraction spectrum is shown in FIG. 12, and a differential scanningcalorimetry (DSC) chart is shown in FIG. 13, respectively. In addition,a diffraction angle 2θ and a relative intensity in the powder X-raydiffraction spectrum are shown in the following Table.

Powder X-Ray Diffraction Spectrum:

TABLE 6 Diffraction angle 2θ (degree) Relative intensity (%) 5.588 43.77.811 22.1 8.415 13.5 9.038 15.8 9.666 15.4 10.99 20.3 11.76 14.3 12.06520.1 12.597 24.3 13.206 20.3 13.656 17.6 14.179 60.8 14.482 77.6 14.66981.6 15.234 89.2 16.531 100 17.068 41.7 17.76 21.5 18.041 32 18.735 37.319.001 29.3 19.413 22.1 20.015 35.5 21.19 22.1 21.685 32.9 22.332 23.922.124 27.7 23.708 18.8 24.245 25.9

The present crystal showed an endothermic peak corresponding to meltingat about 60° C.

Pharmacological Experimental Example (1) In Vitro Test (1-1) Measurementof Agonist Activity on Various Mouse Prostanoid Receptors

Using CHO cells (FP-CHO, EPI-CHO and IP-CHO, respectively) in whichvarious mouse prostanoid receptors were forcibly expressed,respectively, agonist activity of test compounds on various prostanoidreceptors was studied employing an intracellular calcium concentrationregarding FP and EP1, and an intracellular cyclic AMP (hereinafter,abbreviated as cAMP) production amount regarding IP, as an index.

<Compound Treatment>

The test compound and a control substance (PGE₂ and iroprost) weredissolved with dimethyl sulfoxide (DMSO) to prepare a 10 mmol/Lsolution. Regarding the prepared 10 mmol/L solution, upon use, the 10mmol/L solution was thawed, stepwisely-diluted using DMSO, and dilutedwith a buffer solution for measurement or a buffer solution formeasurement 2, which was subjected to an experiment.

<Cell Culturing>

Cells forcibly expressing various mouse prostanoid receptors werestanding-cultured at 37° C. in the presence of 5% CO₂ using an α-MEMmedium (Sigma) (for culturing FP-CHO and EP1-CHO) containing inactivated(56° C., 30 minutes) 9.8 vol % dialysed-FBS (Invitrogen) andpenicillin-streptomycin-glutamine (GIBCO-BRL), or nucleicacid-containing α-MEM (Sigma) (for culturing IP-CHO) containinginactivated (56° C., 30 minutes) 9.8 vol % dialysed-FBS (Invitrogen) andpenicillin-streptomycin glutamine (Invitrogen). Subculturing wasperformed by the following method.

The medium was removed, and washed with a phosphate-bufferedphysiological saline not containing Ca²⁺ and Mg²⁺ two times. A suitableamount of trypsin-EDTA (Invitrogen) was added, this was incubated at 37°C. for about 3 minutes, cells were peeled, and a medium having a volumewhich is 10-fold a volume of trypsin-EDTA was added to stop an enzymaticreaction. After cells were recovered (120 g) into a centrifuging tube,and centrifuged at room temperature for 3 minutes, the supernatant wasremoved. Cells were suspended in a suitable amount of a medium, andseeded in a culturing flask.

(1-2) Measurement of FP and EP1 Agonist Activity (Measurement ofIntracellular Calcium Concentration)

Regarding FP-CHO and EP1-CHO, by the same method as that ofsubculturing, cells were peeled and suspended and, before two days frommeasurement, the suspension was seeded on a 96-well UV plate so that thecell number per well became 1.0×10⁴, and standing-cultured at 37° C. inthe presence of 5% CO₂. On the measurement day, after the medium wasremoved from each well of the 96-well UV plate, each well was washedwith a phosphate-buffered physiological saline not containing Ca²⁺ andMg²⁺ once. To each well was added 100 μL of a medium containing 5 μmol/Lfura 2-AM (DOJINDO), 2.5 mmol/L Probenecid (Sigma), 20 μmol/Lindometacin (Sigma) and 10 mmol/L HEPES (Invitrogen), and this wasincubated for about 60 minutes in a CO₂ incubator. After completion ofthe incubation, the medium was removed, and this was washed with abuffer solution for measurement (Hank's balanced salt solution (NissuiPharmaceutical Co., Ltd., 9.8 g of the present product was dissolved in1 L distilled water) containing 0.1 or 1 w/v % bovine serum albumin, 2μmol/L indometacin, 2.5 mmol/L Probenecid and 10 mmol/L HEPES-NaOH (pH7.4)) two times. To each well was added 120 L of a buffer solution formeasurement, and this was allowed to stand in a CO₂ incubator for 30minutes, and stabilized, which was subjected to an experiment.

The 96-well UV plate was set in a fluorescent spectral photometer(FDSS-3000, Hamamatsu Photonics K.K.), and an intracellular calciumconcentration was measured. A buffered solution for measurement (30 μL)containing an agonist at a variety of concentrations was added toperform a reaction. Measurement of an intracellular calciumconcentration was performed by irradiating cells with excited light of340 nm and 380 nm alternately, measuring a fluorescent intensity at 500nm, and obtaining a fluorescent intensity ratio of 2-wavelengthexcitation.

(1-3) Measurement of IP Agonist Activity (Measurement of cAMPConcentration)

On the measurement day, a medium was removed, and IP-CHO was washed witha phosphate-buffered physiological saline containing EDTA and notcontaining Ca²⁺ and Mg²⁺ once. A suitable amount of a phosphate-bufferedphysiological containing 2 mmol/L EDTA and not containing Ca²⁺ and Mg²⁺was added, this was incubated at 37° C. for about 10 minutes, cells werepeeled, cells were recovered (500 g) into a centrifuging tube, andcentrifuged at room temperature for 3 minutes, and the supernatant wasremoved. Cells were suspended in a suitable amount of a buffer solutionfor measurement 1 (MEM medium (Invitrogen) containing 0.1 w/v % bovineserum albumin (Sigma) and 2 μmol/L diclofenac (Sigma)), and centrifugedat room temperature for 3 minutes at 500 g, and the supernatant wasremoved. Cells were suspended in a buffer solution for measurement 2(MEM medium (Invitrogen) containing 0.1 w/v % bovine serum albumin(Sigma), 2 μmol/L diclofenac (Sigma) and 1 mmol/L3-isobutyl-1-methylxanthine), and each 25 μL of the suspension wasdispensed into a 96-well ½ area plate so that the cell number per wellbecame 5.0×10⁴. A buffer solution for measurement 2 (25 μL) containingan agonist at a variety of concentrations was added to perform areaction at room temperature for 30 minutes. Measurement of a cAMPconcentration was performed using the cAMP HTRF HiRange kit (CIS bioInternational). According to the two step protocol of the kit manual,each 25 L of cAMP-D2 and cryptase diluted with a lysis buffer wereadded, and this was incubated at room temperature for 1 hour. Afterincubation for 1 hour, time resolution fluorescence at 620 nm and 660 nmwhen excited at 340 nm was measured using Analyst GF (Molecular Device),and a ratio (TRF ratio) was obtained, thereby, a cAMP concentration wascalculated from a calibration line.

<Result>

Using measured values obtained from the above method, an EC₅₀ value asan index of agonist activity of the present invention compound on mouseFP, mouse EP1 and mouse IP receptors was calculated.

For example, results of the compound described in Example 17 (23), thecompound described in Example 17 (3), the compound described in Example17 (4), the compound described in Example 17 (25), the compounddescribed in Example 29 (12), the compound described in Example 32 and,as a comparative compound, the compound of Example 12 described inPatent Literature 2 shown by the following structural formula(hereinafter, abbreviated as Comparative Example A in some cases) areshown in Table 7.

TABLE 7 Agonist activity on various prostanoid receptors: EC₅₀ value(nmol/L) FP EP1 IP Example 17 (23) 8.3 100 >10000 Example 17 (3) 3.03200 >10000 Example 17 (4) 8.8 >10000 >10000 Example 17 (25) 2.4857 >10000 Example 29 (12) 7.1 >10000 >10000 Example 321.6 >10000 >10000 Comparative Compound A 1.1 3 710

From the above results, it was seen that the Comparative Compound A hasagonist activity not only on a FP receptor, but also on an EP1 receptorand an IP receptor, while all of the present invention compounds havelow agonist activity on an EP1 receptor and an IP receptor, and haveselective agonist activity on a FP receptor.

(2) In Vivo Test

As can be easily understood by a person skilled in the art, in an invivo test, since regarding all test compounds, carboxylic acid which isan active body has bad corneal permeability, pharmacological action wasassessed by ocular instillation administration of a compound which hadbeen converted into an ester such as an ethyl ester, an isopropyl esteretc. In addition, in a group of the present invention compounds, byocular instillation-administering the ester body in an experimentalanimal (rabbit, dog etc.) by which pharmacological action is confirmedbelow and, thereafter, measuring a drug concentration of carboxylic acidin an aqueous humor, it was confirmed that the ester is rapidlyconverted into corresponding carboxylic acid.

(2-1) Intraocular Pressure Lowering Action

To one eye of a male dog (TOYO Beagle) which had been sufficientlyacclimated in advance was ocular-instilled 30 μL of each test compound(compound of Example 16 (35) and compound of Example 16 (3)) which hadbeen adjusted with a base (containing citrate buffer pH 6.5, 0.5%polysorbate 80, 1% propylene glycol, 0.01% benzalkonium chloride) to0.01% (w/v) or 0.001% (w/v), respectively. The other eye was nottreated. As a positive control compound, latanoprost which is the knowncompound was used.

Thereafter, an ocular surface anesthetic (Benoxil eye drops 0.4%, SantenPharmaceutical Co., Ltd.) was subjected to ocular instillation tolocally anesthetize eyes, and an intraocular pressure of each testcompound before ocular instillation and after 2, 4, 6, 8, and 24 hoursfrom ocular instillation was measured. An intraocular pressure wasmeasured using a pneumatic applanation flat tonometer (Model 30 Classic,REICHERT). An intraocular pressure lowering rate (%) was calculated bythe following equation.

Intraocular pressure lowering rate (%)=(intraocular pressure valuebefore ocular instillation−intraocular pressure value at eachpoint)/(intraocular pressure value before ocularinstillation)×100  [Mathematic 1]

Among measured values at each point, the result showing the maximumaction is shown in Table 8. An intraocular pressure of dogs to whicheach of the compound of Example 16 (35), the compound of Example 16 (3)and the compound of Example 16 (25) was ocular instillation-administeredexhibited the stronger intraocular pressure lowering action as comparedwith latanoprost which is a positive control compound.

TABLE 8 Maximum of Administration Number of intraocular pressureCompound dose (μg/mL) examples lowering rate (%) Example 16 (35) 10 5 31Example 16 (3) 10 5 35.7 Example 16 (25) 10 5 40.6 Latanoprost 50 1025.4

(2-2) Assessment of Ocular Stimulating Property and Aqueous HumorProtein Concentration

To one eye of a male rabbit (NewZealandWhite, 2.0 to 3.0 kg) wasocular-instilled μL of the compound of Example 16 (35), the compound ofExample 16 (3) and the compound of Example 16 (25) which had beenadjusted to 0.1% (w/v) with a base (containing citrate buffer pH 6.5,0.5% polysorbate 80, 1% propylene glycol, 0.01% benzalkonium chloride),respectively. Thereafter, an aqueous humor in anterior chamber after 0,1, 2, 4, 6 and 8 hours from ocular instillation was collected, and aprotein concentration in the humor was measured. As a comparativecompound, the aforementioned methyl ester of the compound of Example 12described in Patent Literature 2 (i.e. compound of Example 10 describedin Patent Literature 2) (hereinafter, abbreviated as ComparativeCompound B in some cases) was used.

Observation of the ocular general state was performed after 0, 1, 2, 4,6 and 8 hours from ocular instillation, and visual remark of cornea,iris, and conjunctiva was observed according to determination criteriaof the Draize method. A total of points of the resulting assessmentpoints of each item (=A₁×B₁×5+A₂×5+(A₃+B₃+C₃)×2) was assessed as aDraize score. Classification criteria of the Draize score was producedby referring to “Regarding Reference Material concerning Basic Idea ofBiological Safety Test, Administrative Notice Medical Device ExaminationNo. 36 dated Mar. 19, 2003, Pharmaceutical and Medical Devices Agency”.Classification criteria was as follows: A Draize score of 0 or more and5 or less was a non-stimulating substance, 5 or more and 15 or less wasa slightly stimulating substance, 15 or more and 30 or less was astimulating substance, 30 or more and 60 or less was an intermediatestimulating substance, 60 or more and 80 or less was an intermediate tostrongly stimulating substance, and 80 or more and 110 or less was astrongly stimulating substance.

Regarding any test compound, a dose until a dissolution limit (150 to1000 μg/mL) was administered and action of each active body wasassessed.

Results are shown in the following FIG. 1 and FIG. 2. The ComparativeCompound B was classified as a slightly stimulating substance from amaximum of the Draize score, based on its agonist activity on an IPreceptor and, further, since it also raises a protein concentration inan aqueous humor, it was seen that it induces the side effect on eyes.To the contrary, it was seen that all of the compounds of Example 16(35), Example 16 (3) and Example 16 (25) which are the present inventioncompounds were a non-stimulating substance by the Draize score, and hadno action of raising a protein concentration in an aqueous humor.

From the foregoing, since the present invention compound has low agonistactivity on an EP1 receptor and an IP receptor, and has selectiveagonist activity on a FP receptor, it was suggested that not only it hasstrong intraocular pressure lowering action, but also side effects oneyes such as ocular itching action based on EP1 receptor agonistactivity, and ocular stimulating property such as hyperemia etc. andaqueous humor protein rise etc. based on IP receptor agonist activitycan be avoided.

(2-3) Intraocular Pressure Lowering Action in Monkey Under Consciousness

To a left eye of a male monkey (crab-eating monkey) under consciousnesswas ocular instillation-administered 30 μL of a solution obtained byadjusting a test substance using the same base as that described aboveand, to a right eye was ocular instillation-administered 30 μL of asolution of only a base as a control, respectively. An intraocularpressure after administration was measured with time from administrationinitiation to after 24 hours. Upon measurement of an intraocularpressure, a crab-eating monkey was fixed on a monkey chair, and themonkey was anesthetized by ocular instillation-administering an ocularsurface anesthetic (Benoxil eye drops 0.4% Santen Pharmaceutical Co.,Ltd.). After mounting of a blepharostat (Handaya Co., Ltd.), anintraocular pressure of both eyes was measured (5 to 8 examples pergroup) using a pneumatic applanation flat tonometer (Model 30 Classic,REICHERT). A difference in an intraocular pressure value between controleyes and eyes to which a test substance had been administered, wascalculated as an intraocular pressure lowering rate using the followingequation, and sustainability of intraocular eye lowering action wasassessed using a maximum intraocular pressure lowering rate duringmeasurement and an intraocular pressure lowering rate after 24 hours. Asthe test substance, the Comparative Compound B, and the compounds ofExample 16 (3), Example 16 (25) and Example 16 (35) were used, and anadministration dose was 10 μg/mL in all cases.

Intraocular pressure lowering rate (%)=(intraocular pressure value ofcontrol eyes−intraocular pressure value of test substance-administeredeyes)/(intraocular pressure value of control eyes)×100  [Mathematic 2]

The results are shown in the following Table 9. It was seen that, in theComparative Compound B, a maximum intraocular pressure lowering rate wasinsufficient and, additionally, the lowering rate was reduced to lessthan 10% after 24 hours, and intraocular pressure lowering action cannotbe sufficiently maintained. To the contrary, it was seen that all of thepresent invention compounds are compounds which have a high maximumintraocular pressure lowering rate, and can maintain an intraocularpressure lowering rate of about 15% or more even after 24 hours, andhave strong and sustaining intraocular pressure lowering action.

TABLE 9 Maximum Intraocular pressure Number of intraocular pressurelowering rate after Compound examples lowering rate (%) 24 hours (%)Comparative 5 13.2 ± 3.2  7.0 ± 0.9 Compound B Example 16 (35) 5 19.2 ±2.6 14.9 ± 4.7 Example 16 (3) 8 28.8 ± 2.2 15.1 ± 2.0 Example 16 (25) 826.5 ± 1.7 17.5 ± 2.1

PREPARATION EXAMPLES

Representative preparation examples used in the present invention willbe shown below.

Preparation Example 1: Eye Drops

Eye drops according to the following formulation was prepared using thegeneral-use method.

After glycerin (2.5 g) and polysorbate 80 (500 mg) were added to sterilepurified water, the compound (1 mg) of Example 16 (35) was added todissolve, sterile purified water was added to a total amount of 100 mL,and this was sterile-filtered with a membrane filter, and filled into apredetermined container to obtain eye drops of the followingformulation.

According to the same manner as that described above, eye drops etc.containing 0.1 mg and 0.5 mg of the compound of Example 16 (35) in 100mL can be prepared.

Alternatively, other present invention compound can be used in place ofthe compound of Example 16 (35).

Preparation Example 2: Ocular Ointment

An ocular ointment of the following formulation was prepared using thegeneral-use method.

A liquid paraffin and white vaseline were heat-sterilized in advance.After the compound (1 mg) of Example 16 (35) was sufficiently kneadedwith a liquid paraffin (10 g), white vaseline was added to a totalamount of 100 g, and the materials were sufficiently kneaded to obtainan ocular ointment of the following formulation.

INDUSTRIAL APPLICABILITY

Since the present invention compound has strong sustaining intraocularpressure lowering action and, further, has no side effects of eyes suchas ocular stimulating property (hyperemia, corneal clouding etc.),aqueous humor protein rise etc., it is useful as an excellent agent forpreventing and/or treating glaucoma etc.

1. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, or a solvate thereof:

and a pharmaceutically acceptable solvent, wherein the composition is a parenteral solution. 